TY - JOUR T1 - Boy with fish-mouth meatus. JF - Arch Dis Child Y1 - 2018 A1 - Cortellazzo Wiel, Luisa A1 - Pederiva, Federica A1 - Castagnetti, Marco A1 - Barbi, Egidio A1 - Pennesi, Marco U1 - http://www.ncbi.nlm.nih.gov/pubmed/29903890?dopt=Abstract ER - TY - JOUR T1 - Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. JF - Genome Biol Y1 - 2018 A1 - Prins, Bram P A1 - Mead, Timothy J A1 - Brody, Jennifer A A1 - Sveinbjornsson, Gardar A1 - Ntalla, Ioanna A1 - Bihlmeyer, Nathan A A1 - van den Berg, Marten A1 - Bork-Jensen, Jette A1 - Cappellani, Stefania A1 - Van Duijvenboden, Stefan A1 - Klena, Nikolai T A1 - Gabriel, George C A1 - Liu, Xiaoqin A1 - Gulec, Cagri A1 - Grarup, Niels A1 - Haessler, Jeffrey A1 - Hall, Leanne M A1 - Iorio, Annamaria A1 - Isaacs, Aaron A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Liu, Ching-Ti A1 - Lyytikäinen, Leo-Pekka A1 - Marten, Jonathan A1 - Mei, Hao A1 - Müller-Nurasyid, Martina A1 - Orini, Michele A1 - Padmanabhan, Sandosh A1 - Radmanesh, Farid A1 - Ramirez, Julia A1 - Robino, Antonietta A1 - Schwartz, Molly A1 - van Setten, Jessica A1 - Smith, Albert V A1 - Verweij, Niek A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Alonso, Alvaro A1 - Arnar, David O A1 - Bots, Michiel L A1 - de Boer, Rudolf A A1 - Dominiczak, Anna F A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Guo, Xiuqing A1 - Felix, Stephan B A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Huang, Paul L A1 - Jukema, J W A1 - Kähönen, Mika A1 - Kors, Jan A A1 - Lambiase, Pier D A1 - Launer, Lenore J A1 - Li, Man A1 - Linneberg, Allan A1 - Nelson, Christopher P A1 - Pedersen, Oluf A1 - Perez, Marco A1 - Peters, Annette A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rice, Kenneth M A1 - Rotter, Jerome I A1 - Sinner, Moritz F A1 - Soliman, Elsayed Z A1 - Spector, Tim D A1 - Strauch, Konstantin A1 - Thorsteinsdottir, Unnur A1 - Tinker, Andrew A1 - Trompet, Stella A1 - Uitterlinden, André A1 - Vaartjes, Ilonca A1 - van der Meer, Peter A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wilson, James G A1 - Xie, Zhijun A1 - Asselbergs, Folkert W A1 - Dörr, Marcus A1 - van Duijn, Cornelia M A1 - Gasparini, Paolo A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Kääb, Stefan A1 - Kanters, Jørgen K A1 - Kooperberg, Charles A1 - Lehtimäki, Terho A1 - Lin, Henry J A1 - Lubitz, Steven A A1 - Mook-Kanamori, Dennis O A1 - Conti, Francesco J A1 - Newton-Cheh, Christopher H A1 - Rosand, Jonathan A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Sinagra, Gianfranco A1 - Smith, Blair H A1 - Holm, Hilma A1 - Stricker, Bruno H A1 - Ulivi, Sheila A1 - Sotoodehnia, Nona A1 - Apte, Suneel S A1 - van der Harst, Pim A1 - Stefansson, Kari A1 - Munroe, Patricia B A1 - Arking, Dan E A1 - Lo, Cecilia W A1 - Jamshidi, Yalda KW - ADAMTS Proteins KW - African Continental Ancestry Group KW - Animals KW - Connexin 43 KW - Electrocardiography KW - European Continental Ancestry Group KW - Exome KW - Female KW - Gene Expression KW - Gene Expression Profiling KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - Mice KW - Middle Aged KW - Myocardium KW - Open Reading Frames KW - Polymorphism, Single Nucleotide KW - Whole Exome Sequencing AB -

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear.

RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction.

CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

VL - 19 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30012220?dopt=Abstract ER - TY - JOUR T1 - Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals. JF - Nat Genet Y1 - 2018 A1 - Lee, James J A1 - Wedow, Robbee A1 - Okbay, Aysu A1 - Kong, Edward A1 - Maghzian, Omeed A1 - Zacher, Meghan A1 - Nguyen-Viet, Tuan Anh A1 - Bowers, Peter A1 - Sidorenko, Julia A1 - Karlsson Linnér, Richard A1 - Fontana, Mark Alan A1 - Kundu, Tushar A1 - Lee, Chanwook A1 - Li, Hui A1 - Li, Ruoxi A1 - Royer, Rebecca A1 - Timshel, Pascal N A1 - Walters, Raymond K A1 - Willoughby, Emily A A1 - Yengo, Loic A1 - Alver, Maris A1 - Bao, Yanchun A1 - Clark, David W A1 - Day, Felix R A1 - Furlotte, Nicholas A A1 - Joshi, Peter K A1 - Kemper, Kathryn E A1 - Kleinman, Aaron A1 - Langenberg, Claudia A1 - Mägi, Reedik A1 - Trampush, Joey W A1 - Verma, Shefali Setia A1 - Wu, Yang A1 - Lam, Max A1 - Zhao, Jing Hua A1 - Zheng, Zhili A1 - Boardman, Jason D A1 - Campbell, Harry A1 - Freese, Jeremy A1 - Harris, Kathleen Mullan A1 - Hayward, Caroline A1 - Herd, Pamela A1 - Kumari, Meena A1 - Lencz, Todd A1 - Luan, Jian'an A1 - Malhotra, Anil K A1 - Metspalu, Andres A1 - Milani, Lili A1 - Ong, Ken K A1 - Perry, John R B A1 - Porteous, David J A1 - Ritchie, Marylyn D A1 - Smart, Melissa C A1 - Smith, Blair H A1 - Tung, Joyce Y A1 - Wareham, Nicholas J A1 - Wilson, James F A1 - Beauchamp, Jonathan P A1 - Conley, Dalton C A1 - Esko, Tõnu A1 - Lehrer, Steven F A1 - Magnusson, Patrik K E A1 - Oskarsson, Sven A1 - Pers, Tune H A1 - Robinson, Matthew R A1 - Thom, Kevin A1 - Watson, Chelsea A1 - Chabris, Christopher F A1 - Meyer, Michelle N A1 - Laibson, David I A1 - Yang, Jian A1 - Johannesson, Magnus A1 - Koellinger, Philipp D A1 - Turley, Patrick A1 - Visscher, Peter M A1 - Benjamin, Daniel J A1 - Cesarini, David AB -

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

VL - 50 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30038396?dopt=Abstract ER - TY - JOUR T1 - Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. JF - Nat Genet Y1 - 2018 A1 - Evangelou, Evangelos A1 - Warren, Helen R A1 - Mosen-Ansorena, David A1 - Mifsud, Borbala A1 - Pazoki, Raha A1 - Gao, He A1 - Ntritsos, Georgios A1 - Dimou, Niki A1 - Cabrera, Claudia P A1 - Karaman, Ibrahim A1 - Ng, Fu Liang A1 - Evangelou, Marina A1 - Witkowska, Katarzyna A1 - Tzanis, Evan A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - Velez Edwards, Digna R A1 - Sun, Yan V A1 - Cho, Kelly A1 - Gaziano, J Michael A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Kovesdy, Csaba P A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Milani, Lili A1 - Almgren, Peter A1 - Boutin, Thibaud A1 - Debette, Stéphanie A1 - Ding, Jun A1 - Giulianini, Franco A1 - Holliday, Elizabeth G A1 - Jackson, Anne U A1 - Li-Gao, Ruifang A1 - Lin, Wei-Yu A1 - Luan, Jian'an A1 - Mangino, Massimo A1 - Oldmeadow, Christopher A1 - Prins, Bram Peter A1 - Qian, Yong A1 - Sargurupremraj, Muralidharan A1 - Shah, Nabi A1 - Surendran, Praveen A1 - Thériault, Sébastien A1 - Verweij, Niek A1 - Willems, Sara M A1 - Zhao, Jing-Hua A1 - Amouyel, Philippe A1 - Connell, John A1 - de Mutsert, Renée A1 - Doney, Alex S F A1 - Farrall, Martin A1 - Menni, Cristina A1 - Morris, Andrew D A1 - Noordam, Raymond A1 - Paré, Guillaume A1 - Poulter, Neil R A1 - Shields, Denis C A1 - Stanton, Alice A1 - Thom, Simon A1 - Abecasis, Goncalo A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ayers, Kristin L A1 - Barbieri, Caterina M A1 - Batini, Chiara A1 - Bis, Joshua C A1 - Blake, Tineka A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brumat, Marco A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chauhan, Ganesh A1 - Ciullo, Marina A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Cordell, Heather J A1 - Davies, Gail A1 - de Borst, Martin H A1 - de Geus, Eco J A1 - Deary, Ian J A1 - Deelen, Joris A1 - del Greco M, Fabiola A1 - Demirkale, Cumhur Yusuf A1 - Dörr, Marcus A1 - Ehret, Georg B A1 - Elosua, Roberto A1 - Enroth, Stefan A1 - Erzurumluoglu, A Mesut A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Franco, Oscar H A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gow, Alan J A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Harris, Sarah E A1 - Hartman, Catharina A A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hofer, Edith A1 - Hofman, Albert A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Ingelsson, Erik A1 - James, Alan A1 - Jansen, Rick A1 - Järvelin, Marjo-Riitta A1 - Joehanes, Roby A1 - Johansson, Åsa A1 - Johnson, Andrew D A1 - Joshi, Peter K A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Keavney, Bernard D A1 - Khaw, Kay-Tee A1 - Knekt, Paul A1 - Knight, Joanne A1 - Kolcic, Ivana A1 - Kooner, Jaspal S A1 - Koskinen, Seppo A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Laan, Maris A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lopez, Lorna M A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Mamasoula, Chrysovalanto A1 - Marrugat, Jaume A1 - Marten, Jonathan A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew P A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nalls, Mike A A1 - Nandakumar, Priyanka A1 - Nelson, Christopher P A1 - Niiranen, Teemu A1 - Nolte, Ilja M A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - O'Reilly, Paul F A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Palotie, Aarno A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Nguyen, Quang Tri A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rettig, Rainer A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Ried, Janina S A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia F A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Schmidt, Helena A1 - Shrine, Nick A1 - Siscovick, David A1 - Smith, Albert V A1 - Snieder, Harold A1 - Sõber, Siim A1 - Sorice, Rossella A1 - Starr, John M A1 - Stott, David J A1 - Strachan, David P A1 - Strawbridge, Rona J A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Tobin, Martin D A1 - Tomaszewski, Maciej A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Trompet, Stella A1 - Tuomilehto, Jaakko A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Vaez, Ahmad A1 - van der Most, Peter J A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Verwoert, Germaine C A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Yao, Jie A1 - Zemunik, Tatijana A1 - Zhang, Weihua A1 - Attia, John R A1 - Butterworth, Adam S A1 - Chasman, Daniel I A1 - Conen, David A1 - Cucca, Francesco A1 - Danesh, John A1 - Hayward, Caroline A1 - Howson, Joanna M M A1 - Laakso, Markku A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Melander, Olle A1 - Mook-Kanamori, Dennis O A1 - Palmer, Colin N A A1 - Risch, Lorenz A1 - Scott, Robert A A1 - Scott, Rodney J A1 - Sever, Peter A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Zeggini, Eleftheria A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Brown, Morris J A1 - Metspalu, Andres A1 - Hung, Adriana M A1 - O'Donnell, Christopher J A1 - Edwards, Todd L A1 - Psaty, Bruce M A1 - Tzoulaki, Ioanna A1 - Barnes, Michael R A1 - Wain, Louise V A1 - Elliott, Paul A1 - Caulfield, Mark J AB -

High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

VL - 50 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30224653?dopt=Abstract ER - TY - JOUR T1 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. JF - Am J Hum Genet Y1 - 2018 A1 - Ligthart, Symen A1 - Vaez, Ahmad A1 - Võsa, Urmo A1 - Stathopoulou, Maria G A1 - de Vries, Paul S A1 - Prins, Bram P A1 - van der Most, Peter J A1 - Tanaka, Toshiko A1 - Naderi, Elnaz A1 - Rose, Lynda M A1 - Wu, Ying A1 - Karlsson, Robert A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Pool, René A1 - Zhu, Gu A1 - Macé, Aurélien A1 - Sidore, Carlo A1 - Trompet, Stella A1 - Mangino, Massimo A1 - Sabater-Lleal, Maria A1 - Kemp, John P A1 - Abbasi, Ali A1 - Kacprowski, Tim A1 - Verweij, Niek A1 - Smith, Albert V A1 - Huang, Tao A1 - Marzi, Carola A1 - Feitosa, Mary F A1 - Lohman, Kurt K A1 - Kleber, Marcus E A1 - Milaneschi, Yuri A1 - Mueller, Christian A1 - Huq, Mahmudul A1 - Vlachopoulou, Efthymia A1 - Lyytikäinen, Leo-Pekka A1 - Oldmeadow, Christopher A1 - Deelen, Joris A1 - Perola, Markus A1 - Zhao, Jing Hua A1 - Feenstra, Bjarke A1 - Amini, Marzyeh A1 - Lahti, Jari A1 - Schraut, Katharina E A1 - Fornage, Myriam A1 - Suktitipat, Bhoom A1 - Chen, Wei-Min A1 - Li, Xiaohui A1 - Nutile, Teresa A1 - Malerba, Giovanni A1 - Luan, Jian'an A1 - Bak, Tom A1 - Schork, Nicholas A1 - del Greco M, Fabiola A1 - Thiering, Elisabeth A1 - Mahajan, Anubha A1 - Marioni, Riccardo E A1 - Mihailov, Evelin A1 - Eriksson, Joel A1 - Ozel, Ayse Bilge A1 - Zhang, Weihua A1 - Nethander, Maria A1 - Cheng, Yu-Ching A1 - Aslibekyan, Stella A1 - Ang, Wei A1 - Gandin, Ilaria A1 - Yengo, Loic A1 - Portas, Laura A1 - Kooperberg, Charles A1 - Hofer, Edith A1 - Rajan, Kumar B A1 - Schurmann, Claudia A1 - den Hollander, Wouter A1 - Ahluwalia, Tarunveer S A1 - Zhao, Jing A1 - Draisma, Harmen H M A1 - Ford, Ian A1 - Timpson, Nicholas A1 - Teumer, Alexander A1 - Huang, Hongyan A1 - Wahl, Simone A1 - Liu, Yongmei A1 - Huang, Jie A1 - Uh, Hae-Won A1 - Geller, Frank A1 - Joshi, Peter K A1 - Yanek, Lisa R A1 - Trabetti, Elisabetta A1 - Lehne, Benjamin A1 - Vozzi, Diego A1 - Verbanck, Marie A1 - Biino, Ginevra A1 - Saba, Yasaman A1 - Meulenbelt, Ingrid A1 - O'Connell, Jeff R A1 - Laakso, Markku A1 - Giulianini, Franco A1 - Magnusson, Patrik K E A1 - Ballantyne, Christie M A1 - Hottenga, Jouke Jan A1 - Montgomery, Grant W A1 - Rivadineira, Fernando A1 - Rueedi, Rico A1 - Steri, Maristella A1 - Herzig, Karl-Heinz A1 - Stott, David J A1 - Menni, Cristina A1 - Frånberg, Mattias A1 - St Pourcain, Beate A1 - Felix, Stephan B A1 - Pers, Tune H A1 - Bakker, Stephan J L A1 - Kraft, Peter A1 - Peters, Annette A1 - Vaidya, Dhananjay A1 - Delgado, Graciela A1 - Smit, Johannes H A1 - Großmann, Vera A1 - Sinisalo, Juha A1 - Seppälä, Ilkka A1 - Williams, Stephen R A1 - Holliday, Elizabeth G A1 - Moed, Matthijs A1 - Langenberg, Claudia A1 - Räikkönen, Katri A1 - Ding, Jingzhong A1 - Campbell, Harry A1 - Sale, Michele M A1 - Chen, Yii-Der I A1 - James, Alan L A1 - Ruggiero, Daniela A1 - Soranzo, Nicole A1 - Hartman, Catharina A A1 - Smith, Erin N A1 - Berenson, Gerald S A1 - Fuchsberger, Christian A1 - Hernandez, Dena A1 - Tiesler, Carla M T A1 - Giedraitis, Vilmantas A1 - Liewald, David A1 - Fischer, Krista A1 - Mellström, Dan A1 - Larsson, Anders A1 - Wang, Yunmei A1 - Scott, William R A1 - Lorentzon, Matthias A1 - Beilby, John A1 - Ryan, Kathleen A A1 - Pennell, Craig E A1 - Vuckovic, Dragana A1 - Balkau, Beverly A1 - Concas, Maria Pina A1 - Schmidt, Reinhold A1 - Mendes de Leon, Carlos F A1 - Bottinger, Erwin P A1 - Kloppenburg, Margreet A1 - Paternoster, Lavinia A1 - Boehnke, Michael A1 - Musk, A W A1 - Willemsen, Gonneke A1 - Evans, David M A1 - Madden, Pamela A F A1 - Kähönen, Mika A1 - Kutalik, Zoltán A1 - Zoledziewska, Magdalena A1 - Karhunen, Ville A1 - Kritchevsky, Stephen B A1 - Sattar, Naveed A1 - LaChance, Genevieve A1 - Clarke, Robert A1 - Harris, Tamara B A1 - Raitakari, Olli T A1 - Attia, John R A1 - van Heemst, Diana A1 - Kajantie, Eero A1 - Sorice, Rossella A1 - Gambaro, Giovanni A1 - Scott, Robert A A1 - Hicks, Andrew A A1 - Ferrucci, Luigi A1 - Standl, Marie A1 - Lindgren, Cecilia M A1 - Starr, John M A1 - Karlsson, Magnus A1 - Lind, Lars A1 - Li, Jun Z A1 - Chambers, John C A1 - Mori, Trevor A A1 - de Geus, Eco J C N A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Auvinen, Juha A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Waldenberger, Melanie A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Scott, Rodney J A1 - McEvoy, Mark A1 - Beekman, Marian A1 - Bombieri, Cristina A1 - Ridker, Paul M A1 - Mohlke, Karen L A1 - Pedersen, Nancy L A1 - Morrison, Alanna C A1 - Boomsma, Dorret I A1 - Whitfield, John B A1 - Strachan, David P A1 - Hofman, Albert A1 - Vollenweider, Peter A1 - Cucca, Francesco A1 - Järvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Spector, Tim D A1 - Hamsten, Anders A1 - Zeller, Tanja A1 - Uitterlinden, André G A1 - Nauck, Matthias A1 - Gudnason, Vilmundur A1 - Qi, Lu A1 - Grallert, Harald A1 - Borecki, Ingrid B A1 - Rotter, Jerome I A1 - März, Winfried A1 - Wild, Philipp S A1 - Lokki, Marja-Liisa A1 - Boyle, Michael A1 - Salomaa, Veikko A1 - Melbye, Mads A1 - Eriksson, Johan G A1 - Wilson, James F A1 - Penninx, Brenda W J H A1 - Becker, Diane M A1 - Worrall, Bradford B A1 - Gibson, Greg A1 - Krauss, Ronald M A1 - Ciullo, Marina A1 - Zaza, Gianluigi A1 - Wareham, Nicholas J A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Murray, Sarah S A1 - Pramstaller, Peter P A1 - Bandinelli, Stefania A1 - Heinrich, Joachim A1 - Ingelsson, Erik A1 - Deary, Ian J A1 - Mägi, Reedik A1 - Vandenput, Liesbeth A1 - van der Harst, Pim A1 - Desch, Karl C A1 - Kooner, Jaspal S A1 - Ohlsson, Claes A1 - Hayward, Caroline A1 - Lehtimäki, Terho A1 - Shuldiner, Alan R A1 - Arnett, Donna K A1 - Beilin, Lawrence J A1 - Robino, Antonietta A1 - Froguel, Philippe A1 - Pirastu, Mario A1 - Jess, Tine A1 - Koenig, Wolfgang A1 - Loos, Ruth J F A1 - Evans, Denis A A1 - Schmidt, Helena A1 - Smith, George Davey A1 - Slagboom, P Eline A1 - Eiriksdottir, Gudny A1 - Morris, Andrew P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Nolte, Ilja M A1 - Boerwinkle, Eric A1 - Visvikis-Siest, Sophie A1 - Reiner, Alex P A1 - Gross, Myron A1 - Bis, Joshua C A1 - Franke, Lude A1 - Franco, Oscar H A1 - Benjamin, Emelia J A1 - Chasman, Daniel I A1 - Dupuis, Josée A1 - Snieder, Harold A1 - Dehghan, Abbas A1 - Alizadeh, Behrooz Z AB -

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

VL - 103 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30388399?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association meta-analysis highlights light-induced signaling as a driver for refractive error. JF - Nat Genet Y1 - 2018 A1 - Tedja, Milly S A1 - Wojciechowski, Robert A1 - Hysi, Pirro G A1 - Eriksson, Nicholas A1 - Furlotte, Nicholas A A1 - Verhoeven, Virginie J M A1 - Iglesias, Adriana I A1 - Meester-Smoor, Magda A A1 - Tompson, Stuart W A1 - Fan, Qiao A1 - Khawaja, Anthony P A1 - Cheng, Ching-Yu A1 - Höhn, René A1 - Yamashiro, Kenji A1 - Wenocur, Adam A1 - Grazal, Clare A1 - Haller, Toomas A1 - Metspalu, Andres A1 - Wedenoja, Juho A1 - Jonas, Jost B A1 - Wang, Ya Xing A1 - Xie, Jing A1 - Mitchell, Paul A1 - Foster, Paul J A1 - Klein, Barbara E K A1 - Klein, Ronald A1 - Paterson, Andrew D A1 - Hosseini, S Mohsen A1 - Shah, Rupal L A1 - Williams, Cathy A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Gupta, Preeti A1 - Zhao, Wanting A1 - Shi, Yuan A1 - Saw, Woei-Yuh A1 - Tai, E-Shyong A1 - Sim, Xue Ling A1 - Huffman, Jennifer E A1 - Polasek, Ozren A1 - Hayward, Caroline A1 - Bencic, Goran A1 - Rudan, Igor A1 - Wilson, James F A1 - Joshi, Peter K A1 - Tsujikawa, Akitaka A1 - Matsuda, Fumihiko A1 - Whisenhunt, Kristina N A1 - Zeller, Tanja A1 - van der Spek, Peter J A1 - Haak, Roxanna A1 - Meijers-Heijboer, Hanne A1 - van Leeuwen, Elisabeth M A1 - Iyengar, Sudha K A1 - Lass, Jonathan H A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Vingerling, Johannes R A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Biino, Ginevra A1 - Concas, Maria Pina A1 - Schwantes-An, Tae-Hwi A1 - Igo, Robert P A1 - Cuellar-Partida, Gabriel A1 - Martin, Nicholas G A1 - Craig, Jamie E A1 - Gharahkhani, Puya A1 - Williams, Katie M A1 - Nag, Abhishek A1 - Rahi, Jugnoo S A1 - Cumberland, Phillippa M A1 - Delcourt, Cécile A1 - Bellenguez, Céline A1 - Ried, Janina S A1 - Bergen, Arthur A A1 - Meitinger, Thomas A1 - Gieger, Christian A1 - Wong, Tien Yin A1 - Hewitt, Alex W A1 - Mackey, David A A1 - Simpson, Claire L A1 - Pfeiffer, Norbert A1 - Pärssinen, Olavi A1 - Baird, Paul N A1 - Vitart, Veronique A1 - Amin, Najaf A1 - van Duijn, Cornelia M A1 - Bailey-Wilson, Joan E A1 - Young, Terri L A1 - Saw, Seang-Mei A1 - Stambolian, Dwight A1 - MacGregor, Stuart A1 - Guggenheim, Jeremy A A1 - Tung, Joyce Y A1 - Hammond, Christopher J A1 - Klaver, Caroline C W AB -

Refractive errors, including myopia, are the most frequent eye disorders worldwide and an increasingly common cause of blindness. This genome-wide association meta-analysis in 160,420 participants and replication in 95,505 participants increased the number of established independent signals from 37 to 161 and showed high genetic correlation between Europeans and Asians (>0.78). Expression experiments and comprehensive in silico analyses identified retinal cell physiology and light processing as prominent mechanisms, and also identified functional contributions to refractive-error development in all cell types of the neurosensory retina, retinal pigment epithelium, vascular endothelium and extracellular matrix. Newly identified genes implicate novel mechanisms such as rod-and-cone bipolar synaptic neurotransmission, anterior-segment morphology and angiogenesis. Thirty-one loci resided in or near regions transcribing small RNAs, thus suggesting a role for post-transcriptional regulation. Our results support the notion that refractive errors are caused by a light-dependent retina-to-sclera signaling cascade and delineate potential pathobiological molecular drivers.

VL - 50 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29808027?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability. JF - Nat Genet Y1 - 2018 A1 - Hysi, Pirro G A1 - Valdes, Ana M A1 - Liu, Fan A1 - Furlotte, Nicholas A A1 - Evans, David M A1 - Bataille, Veronique A1 - Visconti, Alessia A1 - Hemani, Gibran A1 - McMahon, George A1 - Ring, Susan M A1 - Smith, George Davey A1 - Duffy, David L A1 - Zhu, Gu A1 - Gordon, Scott D A1 - Medland, Sarah E A1 - Lin, Bochao D A1 - Willemsen, Gonneke A1 - Jan Hottenga, Jouke A1 - Vuckovic, Dragana A1 - Girotto, Giorgia A1 - Gandin, Ilaria A1 - Sala, Cinzia A1 - Concas, Maria Pina A1 - Brumat, Marco A1 - Gasparini, Paolo A1 - Toniolo, Daniela A1 - Cocca, Massimiliano A1 - Robino, Antonietta A1 - Yazar, Seyhan A1 - Hewitt, Alex W A1 - Chen, Yan A1 - Zeng, Changqing A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Hamer, Merel A A1 - van Duijn, Cornelia M A1 - Nijsten, Tamar A1 - Mackey, David A A1 - Falchi, Mario A1 - Boomsma, Dorret I A1 - Martin, Nicholas G A1 - Hinds, David A A1 - Kayser, Manfred A1 - Spector, Timothy D AB -

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

VL - 50 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29662168?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study of corneal astigmatism: The CREAM Consortium. JF - Mol Vis Y1 - 2018 A1 - Shah, Rupal L A1 - Li, Qing A1 - Zhao, Wanting A1 - Tedja, Milly S A1 - Tideman, J Willem L A1 - Khawaja, Anthony P A1 - Fan, Qiao A1 - Yazar, Seyhan A1 - Williams, Katie M A1 - Verhoeven, Virginie J M A1 - Xie, Jing A1 - Wang, Ya Xing A1 - Hess, Moritz A1 - Nickels, Stefan A1 - Lackner, Karl J A1 - Pärssinen, Olavi A1 - Wedenoja, Juho A1 - Biino, Ginevra A1 - Concas, Maria Pina A1 - Uitterlinden, André A1 - Rivadeneira, Fernando A1 - Jaddoe, Vincent W V A1 - Hysi, Pirro G A1 - Sim, Xueling A1 - Tan, Nicholas A1 - Tham, Yih-Chung A1 - Sensaki, Sonoko A1 - Hofman, Albert A1 - Vingerling, Johannes R A1 - Jonas, Jost B A1 - Mitchell, Paul A1 - Hammond, Christopher J A1 - Höhn, René A1 - Baird, Paul N A1 - Wong, Tien-Yin A1 - Cheng, Chinfsg-Yu A1 - Teo, Yik Ying A1 - Mackey, David A A1 - Williams, Cathy A1 - Saw, Seang-Mei A1 - Klaver, Caroline C W A1 - Guggenheim, Jeremy A A1 - Bailey-Wilson, Joan E KW - Acid Phosphatase KW - Asian Continental Ancestry Group KW - Astigmatism KW - Claudins KW - Cohort Studies KW - Cornea KW - Corneal Diseases KW - European Continental Ancestry Group KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Odds Ratio KW - Polymorphism, Single Nucleotide KW - Receptor, Platelet-Derived Growth Factor alpha KW - Software AB -

Purpose: To identify genes and genetic markers associated with corneal astigmatism.

Methods: A meta-analysis of genome-wide association studies (GWASs) of corneal astigmatism undertaken for 14 European ancestry (n=22,250) and 8 Asian ancestry (n=9,120) cohorts was performed by the Consortium for Refractive Error and Myopia. Cases were defined as having >0.75 diopters of corneal astigmatism. Subsequent gene-based and gene-set analyses of the meta-analyzed results of European ancestry cohorts were performed using VEGAS2 and MAGMA software. Additionally, estimates of single nucleotide polymorphism (SNP)-based heritability for corneal and refractive astigmatism and the spherical equivalent were calculated for Europeans using LD score regression.

Results: The meta-analysis of all cohorts identified a genome-wide significant locus near the platelet-derived growth factor receptor alpha () gene: top SNP: rs7673984, odds ratio=1.12 (95% CI:1.08-1.16), p=5.55×10. No other genome-wide significant loci were identified in the combined analysis or European/Asian ancestry-specific analyses. Gene-based analysis identified three novel candidate genes for corneal astigmatism in Europeans-claudin-7 (), acid phosphatase 2, lysosomal (), and TNF alpha-induced protein 8 like 3 ().

Conclusions: In addition to replicating a previously identified genome-wide significant locus for corneal astigmatism near the gene, gene-based analysis identified three novel candidate genes, , , and , that warrant further investigation to understand their role in the pathogenesis of corneal astigmatism. The much lower number of genetic variants and genes demonstrating an association with corneal astigmatism compared to published spherical equivalent GWAS analyses suggest a greater influence of rare genetic variants, non-additive genetic effects, or environmental factors in the development of astigmatism.

VL - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29422769?dopt=Abstract ER - TY - JOUR T1 - Joint Data Analysis in Nutritional Epidemiology: Identification of Observational Studies and Minimal Requirements. JF - J Nutr Y1 - 2018 A1 - Pinart, Mariona A1 - Nimptsch, Katharina A1 - Bouwman, Jildau A1 - Dragsted, Lars O A1 - Yang, Chen A1 - De Cock, Nathalie A1 - Lachat, Carl A1 - Perozzi, Giuditta A1 - Canali, Raffaella A1 - Lombardo, Rosario A1 - D'Archivio, Massimo A1 - Guillaume, Michèle A1 - Donneau, Anne-Françoise A1 - Jeran, Stephanie A1 - Linseisen, Jakob A1 - Kleiser, Christina A1 - Nöthlings, Ute A1 - Barbaresko, Janett A1 - Boeing, Heiner A1 - Stelmach-Mardas, Marta A1 - Heuer, Thorsten A1 - Laird, Eamon A1 - Walton, Janette A1 - Gasparini, Paolo A1 - Robino, Antonietta A1 - Castaño, Luis A1 - Rojo-Martínez, Gemma A1 - Merino, Jordi A1 - Masana, Luis A1 - Standl, Marie A1 - Schulz, Holger A1 - Biagi, Elena A1 - Nurk, Eha A1 - Matthys, Christophe A1 - Gobbetti, Marco A1 - de Angelis, Maria A1 - Windler, Eberhard A1 - Zyriax, Birgit-Christiane A1 - Tafforeau, Jean A1 - Pischon, Tobias KW - Adult KW - Biomarkers KW - Blood Glucose KW - Case-Control Studies KW - Child KW - Chronic Disease KW - Cohort Studies KW - Cross-Sectional Studies KW - Diet KW - Epidemiology KW - Europe KW - Genomics KW - Health Status KW - Humans KW - Inflammation KW - Insulin KW - Life Style KW - Lipoproteins KW - Longitudinal Studies KW - Metabolomics KW - Nutritional Status KW - Observational Studies as Topic KW - Statistics as Topic AB -

Background: Joint data analysis from multiple nutrition studies may improve the ability to answer complex questions regarding the role of nutritional status and diet in health and disease.

Objective: The objective was to identify nutritional observational studies from partners participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) Consortium, as well as minimal requirements for joint data analysis.

Methods: A predefined template containing information on study design, exposure measurements (dietary intake, alcohol and tobacco consumption, physical activity, sedentary behavior, anthropometric measures, and sociodemographic and health status), main health-related outcomes, and laboratory measurements (traditional and omics biomarkers) was developed and circulated to those European research groups participating in the ENPADASI under the strategic research area of "diet-related chronic diseases." Information about raw data disposition and metadata sharing was requested. A set of minimal requirements was abstracted from the gathered information.

Results: Studies (12 cohort, 12 cross-sectional, and 2 case-control) were identified. Two studies recruited children only and the rest recruited adults. All studies included dietary intake data. Twenty studies collected blood samples. Data on traditional biomarkers were available for 20 studies, of which 17 measured lipoproteins, glucose, and insulin and 13 measured inflammatory biomarkers. Metabolomics, proteomics, and genomics or transcriptomics data were available in 5, 3, and 12 studies, respectively. Although the study authors were willing to share metadata, most refused, were hesitant, or had legal or ethical issues related to sharing raw data. Forty-one descriptors of minimal requirements for the study data were identified to facilitate data integration.

Conclusions: Combining study data sets will enable sufficiently powered, refined investigations to increase the knowledge and understanding of the relation between food, nutrition, and human health. Furthermore, the minimal requirements for study data may encourage more efficient secondary usage of existing data and provide sufficient information for researchers to draft future multicenter research proposals in nutrition.

VL - 148 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29490094?dopt=Abstract ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stéphanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I KW - Blood Pressure KW - Cohort Studies KW - Continental Population Groups KW - Diastole KW - Epistasis, Genetic KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Smoking KW - Systole AB -

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2).

VL - 102 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29455858?dopt=Abstract ER - TY - JOUR T1 - Meconium-stained amniotic fluid: a risk factor for postpartum hemorrhage. JF - Ther Clin Risk Manag Y1 - 2018 A1 - Bouchè, Carlo A1 - Wiesenfeld, Uri A1 - Ronfani, Luca A1 - Simeone, Roberto A1 - Bogatti, Paolo A1 - Skerk, Kristina A1 - Ricci, Giuseppe AB -

Background/aim: Clinical data with respect to the impact of meconium on the risk of maternal hemorrhage are scarce. Therefore, in this study, we aimed to determine whether meconium-stained amniotic fluid (MSAF) represents a risk factor for postpartum hemorrhage (PPH) after vaginal delivery in a large unselected population.

Patients and methods: A retrospective cohort study evaluated 78,542 consecutive women who had a vaginal delivery between 24th and 44th weeks of gestation. The women who had undergone cesarean section were excluded to avoid possible bias. Postpartum blood loss was measured with graduated blood sack. Postpartum blood loss between 1,000 and 2,000 mL and >2,000 mL were classified as moderate and severe PPH, respectively.

Results: A total of 74,144 patients were available for analysis. According to the color of amniotic fluid (AF), two groups of patients were identified: MSAF (n=10,997) and clear AF (n=63,147). The rates of severe and massive PPH were found to be significantly higher in the MSAF group than that of clear AF group (OR=1.3, 95% CI: 1.2-1.5, <0.001 and OR=2.5, 95% CI: 1.5-4.2, <0.001). Operative vaginal delivery rate was found to be higher in the MSAF group than that of clear AF group, but the difference was only borderline significant (OR=1.5, 95% CI: 1.0-2.2, =0.05). There were no significant differences between the MSAF and the clear AF groups with respect to episiotomies, second- or third-degree perineal tears, vaginal-perineal thrombus, cervical lacerations, vaginal births after cesarean section, twin deliveries, and placental retention rates.

Conclusion: To the best of our knowledge, this is the first clinical study that has investigated the role of MSAF as a risk factor for PPH after vaginal delivery in an unselected population. Our results suggest that MSAF is significantly associated with higher risk of moderate and severe PPH than clear AF.

VL - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30254448?dopt=Abstract ER - TY - JOUR T1 - Non-invasive biomarkers of fetal brain development reflecting prenatal stress: An integrative multi-scale multi-species perspective on data collection and analysis. JF - Neurosci Biobehav Rev Y1 - 2018 A1 - Frasch, Martin G A1 - Lobmaier, Silvia M A1 - Stampalija, Tamara A1 - Desplats, Paula A1 - Pallarés, María Eugenia A1 - Pastor, Verónica A1 - Brocco, Marcela A A1 - Wu, Hau-Tieng A1 - Schulkin, Jay A1 - Herry, Christophe L A1 - Seely, Andrew J E A1 - Metz, Gerlinde A S A1 - Louzoun, Yoram A1 - Antonelli, Marta C AB -

Prenatal stress (PS) impacts early postnatal behavioural and cognitive development. This process of 'fetal programming' is mediated by the effects of the prenatal experience on the developing hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). We derive a multi-scale multi-species approach to devising preclinical and clinical studies to identify early non-invasively available pre- and postnatal biomarkers of PS. The multiple scales include brain epigenome, metabolome, microbiome and the ANS activity gauged via an array of advanced non-invasively obtainable properties of fetal heart rate fluctuations. The proposed framework has the potential to reveal mechanistic links between maternal stress during pregnancy and changes across these physiological scales. Such biomarkers may hence be useful as early and non-invasive predictors of neurodevelopmental trajectories influenced by the PS as well as follow-up indicators of success of therapeutic interventions to correct such altered neurodevelopmental trajectories. PS studies must be conducted on multiple scales derived from concerted observations in multiple animal models and human cohorts performed in an interactive and iterative manner and deploying machine learning for data synthesis, identification and validation of the best non-invasive detection and follow-up biomarkers, a prerequisite for designing effective therapeutic interventions.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/29859198?dopt=Abstract ER - TY - JOUR T1 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Goran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Alcohol Drinking KW - Blood Pressure KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

VL - 13 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/29912962?dopt=Abstract ER - TY - JOUR T1 - PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity. JF - Nat Commun Y1 - 2018 A1 - van Setten, Jessica A1 - Brody, Jennifer A A1 - Jamshidi, Yalda A1 - Swenson, Brenton R A1 - Butler, Anne M A1 - Campbell, Harry A1 - Del Greco, Fabiola M A1 - Evans, Daniel S A1 - Gibson, Quince A1 - Gudbjartsson, Daniel F A1 - Kerr, Kathleen F A1 - Krijthe, Bouwe P A1 - Lyytikäinen, Leo-Pekka A1 - Müller, Christian A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Ritchie, Marylyn D A1 - Robino, Antonietta A1 - Smith, Albert V A1 - Steri, Maristella A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Ulivi, Sheila A1 - Verweij, Niek A1 - Yin, Xiaoyan A1 - Arnar, David O A1 - Asselbergs, Folkert W A1 - Bader, Joel S A1 - Barnard, John A1 - Bis, Josh A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Bradford, Yuki A1 - Buckley, Brendan M A1 - Chung, Mina K A1 - Crawford, Dana A1 - den Hoed, Marcel A1 - Denny, Josh C A1 - Dominiczak, Anna F A1 - Ehret, Georg B A1 - Eijgelsheim, Mark A1 - Ellinor, Patrick T A1 - Felix, Stephan B A1 - Franco, Oscar H A1 - Franke, Lude A1 - Harris, Tamara B A1 - Holm, Hilma A1 - Ilaria, Gandin A1 - Iorio, Annamaria A1 - Kähönen, Mika A1 - Kolcic, Ivana A1 - Kors, Jan A A1 - Lakatta, Edward G A1 - Launer, Lenore J A1 - Lin, Honghuang A1 - Lin, Henry J A1 - Loos, Ruth J F A1 - Lubitz, Steven A A1 - Macfarlane, Peter W A1 - Magnani, Jared W A1 - Leach, Irene Mateo A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Munzel, Thomas A1 - Papanicolaou, George J A1 - Peters, Annette A1 - Pfeufer, Arne A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schlessinger, David A1 - Silva Aldana, Claudia T A1 - Sinner, Moritz F A1 - Smith, Jonathan D A1 - Snieder, Harold A1 - Soliman, Elsayed Z A1 - Spector, Timothy D A1 - Stott, David J A1 - Strauch, Konstantin A1 - Tarasov, Kirill V A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - Van Wagoner, David R A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Jan Westra, Harm A1 - Wild, Philipp S A1 - Zeller, Tanja A1 - Alonso, Alvaro A1 - Avery, Christy L A1 - Bandinelli, Stefania A1 - Benjamin, Emelia J A1 - Cucca, Francesco A1 - Dörr, Marcus A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Munroe, Patricia B A1 - Parsa, Afshin A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Schnabel, Renate B A1 - Sinagra, Gianfranco A1 - Stefansson, Kari A1 - Stricker, Bruno H A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Wilson, James F A1 - Gharib, Sina A A1 - de Bakker, Paul I W A1 - Isaacs, Aaron A1 - Arking, Dan E A1 - Sotoodehnia, Nona KW - Atrial Function KW - Atrioventricular Node KW - Electrocardiography KW - Electrophysiological Phenomena KW - Female KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Male KW - Mutation, Missense KW - Risk Factors AB -

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

VL - 9 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30046033?dopt=Abstract ER - TY - JOUR T1 - Quality of care for children with acute malnutrition at health center level in Uganda: a cross sectional study in West Nile region during the refugee crisis. JF - BMC Health Serv Res Y1 - 2018 A1 - Wanzira, Humphrey A1 - Muyinda, Richard A1 - Lochoro, Peter A1 - Putoto, Giovanni A1 - Segafredo, Giulia A1 - Wamani, Henry A1 - Lazzerini, Marzia KW - Child Nutrition Disorders KW - Child, Preschool KW - Cross-Sectional Studies KW - Health Facilities KW - Humans KW - Nutrition Assessment KW - Nutritional Status KW - Prevalence KW - Quality of Health Care KW - Refugee Camps KW - Refugees KW - Uganda AB -

BACKGROUND: Arua district, in Uganda, hosts some of the largest refugee camps in the country. The estimated prevalence of moderate and severe acute malnutrition in children is higher than the national estimates (10.4 and 5.6% respectively, compared to 3.6 and 1.3%). This study aimed at assessing the quality of care provided to children with acute malnutrition at out-patient level in such a setting.

METHODS: Six facilities with the highest number of children with malnutrition were selected. The main tool used was the National Nutrition Service Delivery Assessment Tool, assessing 10 key areas of service delivery and assigned a score as either poor, fair, good or excellent. Health outcomes, quality of case management and data quality were assessed from the health management information system and from the official nutrition registers.

RESULTS: All facilities except two scored either poor or fair under all the 10 assessment areas. Overall, 33/60 (55%) areas scored as poor, 25/60 (41%) as fair, 2/60 (3.3%) as good, and none as excellent. Main gaps identified included: lack of trained staff; disorganised patient flow; poor case management; stock out of essential supplies including ready-to-use therapeutic foods; weak community linkage. A sample coverage of 45.4% (1020/2248) of total children admitted in the district during the 2016 financial year were included. The overall mean cure rate was 52.9% while the default rate was 38.3%. There was great heterogeneity across health facilities in health outcomes, quality of case management, and data quality.

CONCLUSION: This study suggests that quality of care provided to children with malnutrition at health center level is substandard with unacceptable low cure rates. It is essential to identify effective approaches to enhance adherence to national guidelines, provision of essential nutritional commodities, regular monitoring of services and better linkage with the community through village health teams.

VL - 18 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/30016954?dopt=Abstract ER - TY - JOUR T1 - 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function. JF - Sci Rep Y1 - 2017 A1 - Gorski, Mathias A1 - van der Most, Peter J A1 - Teumer, Alexander A1 - Chu, Audrey Y A1 - Li, Man A1 - Mijatovic, Vladan A1 - Nolte, Ilja M A1 - Cocca, Massimiliano A1 - Taliun, Daniel A1 - Gomez, Felicia A1 - Li, Yong A1 - Tayo, Bamidele A1 - Tin, Adrienne A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Attia, John A1 - Biffar, Reiner A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Bottinger, Erwin P A1 - Chen, Ming-Huei A1 - Chouraki, Vincent A1 - Ciullo, Marina A1 - Coresh, Josef A1 - Cornelis, Marilyn C A1 - Curhan, Gary C A1 - d'Adamo, Adamo Pio A1 - Dehghan, Abbas A1 - Dengler, Laura A1 - Ding, Jingzhong A1 - Eiriksdottir, Gudny A1 - Endlich, Karlhans A1 - Enroth, Stefan A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Girotto, Giorgia A1 - Gottesman, Omri A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hancock, Stephen J A1 - Harris, Tamara B A1 - Helmer, Catherine A1 - Höllerer, Simon A1 - Hofer, Edith A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Homuth, Georg A1 - Hu, Frank B A1 - Huth, Cornelia A1 - Hutri-Kähönen, Nina A1 - Hwang, Shih-Jen A1 - Imboden, Medea A1 - Johansson, Åsa A1 - Kähönen, Mika A1 - König, Wolfgang A1 - Kramer, Holly A1 - Krämer, Bernhard K A1 - Kumar, Ashish A1 - Kutalik, Zoltán A1 - Lambert, Jean-Charles A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - de Borst, Martin A1 - Navis, Gerjan A1 - Swertz, Morris A1 - Liu, Yongmei A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - McEvoy, Mark A A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Metzger, Marie A1 - Mihailov, Evelin A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Oldehinkel, Albertine J A1 - Olden, Matthias A1 - Wjh Penninx, Brenda A1 - Pistis, Giorgio A1 - Pramstaller, Peter P A1 - Probst-Hensch, Nicole A1 - Raitakari, Olli T A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Robino, Antonietta A1 - Rosas, Sylvia E A1 - Ruderfer, Douglas A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sala, Cinzia A1 - Schmidt, Helena A1 - Schmidt, Reinhold A1 - Scott, Rodney J A1 - Sedaghat, Sanaz A1 - Smith, Albert V A1 - Sorice, Rossella A1 - Stengel, Bénédicte A1 - Stracke, Sylvia A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Viikari, Jorma S A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Jin Wang, Jie A1 - Yang, Qiong A1 - Chasman, Daniel I A1 - Tromp, Gerard A1 - Snieder, Harold A1 - Heid, Iris M A1 - Fox, Caroline S A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian KW - Computational Biology KW - Gene Frequency KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Genotyping Techniques KW - Humans KW - Kidney KW - Polymorphism, Single Nucleotide AB -

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28452372?dopt=Abstract ER - TY - JOUR T1 - and Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function. JF - J Am Soc Nephrol Y1 - 2017 A1 - Li, Man A1 - Li, Yong A1 - Weeks, Olivia A1 - Mijatovic, Vladan A1 - Teumer, Alexander A1 - Huffman, Jennifer E A1 - Tromp, Gerard A1 - Fuchsberger, Christian A1 - Gorski, Mathias A1 - Lyytikäinen, Leo-Pekka A1 - Nutile, Teresa A1 - Sedaghat, Sanaz A1 - Sorice, Rossella A1 - Tin, Adrienne A1 - Yang, Qiong A1 - Ahluwalia, Tarunveer S A1 - Arking, Dan E A1 - Bihlmeyer, Nathan A A1 - Böger, Carsten A A1 - Carroll, Robert J A1 - Chasman, Daniel I A1 - Cornelis, Marilyn C A1 - Dehghan, Abbas A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Giulianini, Franco A1 - Heid, Iris A1 - Huang, Jinyan A1 - Imboden, Medea A1 - Jackson, Anne U A1 - Jeff, Janina A1 - Jhun, Min A A1 - Katz, Ronit A1 - Kifley, Annette A1 - Kilpeläinen, Tuomas O A1 - Kumar, Ashish A1 - Laakso, Markku A1 - Li-Gao, Ruifang A1 - Lohman, Kurt A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Malerba, Giovanni A1 - Mihailov, Evelin A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Robino, Antonietta A1 - Ruderfer, Douglas A1 - Salvi, Erika A1 - Schick, Ursula M A1 - Schulz, Christina-Alexandra A1 - Smith, Albert V A1 - Smith, Jennifer A A1 - Traglia, Michela A1 - Yerges-Armstrong, Laura M A1 - Zhao, Wei A1 - Goodarzi, Mark O A1 - Kraja, Aldi T A1 - Liu, Chunyu A1 - Wessel, Jennifer A1 - Boerwinkle, Eric A1 - Borecki, Ingrid B A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Braga, Daniele A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carey, David J A1 - Christensen, Cramer A1 - Coresh, Josef A1 - Crook, Errol A1 - Curhan, Gary C A1 - Cusi, Daniele A1 - de Boer, Ian H A1 - de Vries, Aiko P J A1 - Denny, Joshua C A1 - Devuyst, Olivier A1 - Dreisbach, Albert W A1 - Endlich, Karlhans A1 - Esko, Tõnu A1 - Franco, Oscar H A1 - Fulop, Tibor A1 - Gerhard, Glenn S A1 - Glümer, Charlotte A1 - Gottesman, Omri A1 - Grarup, Niels A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Hu, Frank B A1 - Husemoen, Lise Lotte N A1 - Jackson, Rebecca D A1 - Jørgensen, Torben A1 - Jørgensen, Marit E A1 - Kähönen, Mika A1 - Kardia, Sharon L R A1 - König, Wolfgang A1 - Kooperberg, Charles A1 - Kriebel, Jennifer A1 - Launer, Lenore J A1 - Lauritzen, Torsten A1 - Lehtimäki, Terho A1 - Levy, Daniel A1 - Linksted, Pamela A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Lupo, Antonio A1 - Meisinger, Christine A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Nauck, Matthias A1 - Nürnberg, Peter A1 - Orho-Melander, Marju A1 - Parsa, Afshin A1 - Pedersen, Oluf A1 - Peters, Annette A1 - Peters, Ulrike A1 - Polasek, Ozren A1 - Porteous, David A1 - Probst-Hensch, Nicole M A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rettig, Rainer A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rossouw, Jacques E A1 - Schmidt, Frank A1 - Siscovick, David A1 - Soranzo, Nicole A1 - Strauch, Konstantin A1 - Toniolo, Daniela A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Velayutham, Dinesh A1 - Völker, Uwe A1 - Völzke, Henry A1 - Waldenberger, Melanie A1 - Wang, Jie Jin A1 - Weir, David R A1 - Witte, Daniel A1 - Kuivaniemi, Helena A1 - Fox, Caroline S A1 - Franceschini, Nora A1 - Goessling, Wolfram A1 - Köttgen, Anna A1 - Chu, Audrey Y KW - Animals KW - Exome KW - Genetic Loci KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Protein Tyrosine Phosphatases KW - Proto-Oncogene Proteins KW - Son of Sevenless Proteins KW - Zebrafish AB -

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (: 111,666; : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (, , and ; <3.7×10), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, (=5.4×10 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of and -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27920155?dopt=Abstract ER - TY - JOUR T1 - Child and Adolescent Health From 1990 to 2015: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2015 Study. JF - JAMA Pediatr Y1 - 2017 A1 - Kassebaum, Nicholas A1 - Kyu, Hmwe Hmwe A1 - Zoeckler, Leo A1 - Olsen, Helen Elizabeth A1 - Thomas, Katie A1 - Pinho, Christine A1 - Bhutta, Zulfiqar A A1 - Dandona, Lalit A1 - Ferrari, Alize A1 - Ghiwot, Tsegaye Tewelde A1 - Hay, Simon I A1 - Kinfu, Yohannes A1 - Liang, Xiaofeng A1 - Lopez, Alan A1 - Malta, Deborah Carvalho A1 - Mokdad, Ali H A1 - Naghavi, Mohsen A1 - Patton, George C A1 - Salomon, Joshua A1 - Sartorius, Benn A1 - Topor-Madry, Roman A1 - Vollset, Stein Emil A1 - Werdecker, Andrea A1 - Whiteford, Harvey A A1 - Abate, Kalkidan Hasen A1 - Abbas, Kaja A1 - Damtew, Solomon Abrha A1 - Ahmed, Muktar Beshir A1 - Akseer, Nadia A1 - Al-Raddadi, Rajaa A1 - Alemayohu, Mulubirhan Assefa A1 - Altirkawi, Khalid A1 - Abajobir, Amanuel Alemu A1 - Amare, Azmeraw T A1 - Antonio, Carl A T A1 - Arnlöv, Johan A1 - Artaman, Al A1 - Asayesh, Hamid A1 - Avokpaho, Euripide Frinel G Arthur A1 - Awasthi, Ashish A1 - Ayala Quintanilla, Beatriz Paulina A1 - Bacha, Umar A1 - Betsu, Balem Demtsu A1 - Barac, Aleksandra A1 - Bärnighausen, Till Winfried A1 - Baye, Estifanos A1 - Bedi, Neeraj A1 - Bensenor, Isabela M A1 - Berhane, Adugnaw A1 - Bernabe, Eduardo A1 - Bernal, Oscar Alberto A1 - Beyene, Addisu Shunu A1 - Biadgilign, Sibhatu A1 - Bikbov, Boris A1 - Boyce, Cheryl Anne A1 - Brazinova, Alexandra A1 - Hailu, Gessessew Bugssa A1 - Carter, Austin A1 - Castañeda-Orjuela, Carlos A A1 - Catalá-López, Ferrán A1 - Charlson, Fiona J A1 - Chitheer, Abdulaal A A1 - Choi, Jee-Young Jasmine A1 - Ciobanu, Liliana G A1 - Crump, John A1 - Dandona, Rakhi A1 - Dellavalle, Robert P A1 - Deribew, Amare A1 - deVeber, Gabrielle A1 - Dicker, Daniel A1 - Ding, Eric L A1 - Dubey, Manisha A1 - Endries, Amanuel Yesuf A1 - Erskine, Holly E A1 - Faraon, Emerito Jose Aquino A1 - Faro, Andre A1 - Farzadfar, Farshad A1 - Fernandes, Joao C A1 - Fijabi, Daniel Obadare A1 - Fitzmaurice, Christina A1 - Fleming, Thomas D A1 - Flor, Luisa Sorio A1 - Foreman, Kyle J A1 - Franklin, Richard C A1 - Fraser, Maya S A1 - Frostad, Joseph J A1 - Fullman, Nancy A1 - Gebregergs, Gebremedhin Berhe A1 - Gebru, Alemseged Aregay A1 - Geleijnse, Johanna M A1 - Gibney, Katherine B A1 - Gidey Yihdego, Mahari A1 - Ginawi, Ibrahim Abdelmageem Mohamed A1 - Gishu, Melkamu Dedefo A1 - Gizachew, Tessema Assefa A1 - Glaser, Elizabeth A1 - Gold, Audra L A1 - Goldberg, Ellen A1 - Gona, Philimon A1 - Goto, Atsushi A1 - Gugnani, Harish Chander A1 - Jiang, Guohong A1 - Gupta, Rajeev A1 - Tesfay, Fisaha Haile A1 - Hankey, Graeme J A1 - Havmoeller, Rasmus A1 - Hijar, Martha A1 - Horino, Masako A1 - Hosgood, H Dean A1 - Hu, Guoqing A1 - Jacobsen, Kathryn H A1 - Jakovljevic, Mihajlo B A1 - Jayaraman, Sudha P A1 - Jha, Vivekanand A1 - Jibat, Tariku A1 - Johnson, Catherine O A1 - Jonas, Jost A1 - Kasaeian, Amir A1 - Kawakami, Norito A1 - Keiyoro, Peter N A1 - Khalil, Ibrahim A1 - Khang, Young-Ho A1 - Khubchandani, Jagdish A1 - Ahmad Kiadaliri, Aliasghar A A1 - Kieling, Christian A1 - Kim, Daniel A1 - Kissoon, Niranjan A1 - Knibbs, Luke D A1 - Koyanagi, Ai A1 - Krohn, Kristopher J A1 - Kuate Defo, Barthelemy A1 - Kucuk Bicer, Burcu A1 - Kulikoff, Rachel A1 - Kumar, G Anil A1 - Lal, Dharmesh Kumar A1 - Lam, Hilton Y A1 - Larson, Heidi J A1 - Larsson, Anders A1 - Laryea, Dennis Odai A1 - Leung, Janni A1 - Lim, Stephen S A1 - Lo, Loon-Tzian A1 - Lo, Warren D A1 - Looker, Katharine J A1 - Lotufo, Paulo A A1 - Magdy Abd El Razek, Hassan A1 - Malekzadeh, Reza A1 - Markos Shifti, Desalegn A1 - Mazidi, Mohsen A1 - Meaney, Peter A A1 - Meles, Kidanu Gebremariam A1 - Memiah, Peter A1 - Mendoza, Walter A1 - Abera Mengistie, Mubarek A1 - Mengistu, Gebremichael Welday A1 - Mensah, George A A1 - Miller, Ted R A1 - Mock, Charles A1 - Mohammadi, Alireza A1 - Mohammed, Shafiu A1 - Monasta, Lorenzo A1 - Mueller, Ulrich A1 - Nagata, Chie A1 - Naheed, Aliya A1 - Nguyen, Grant A1 - Nguyen, Quyen Le A1 - Nsoesie, Elaine A1 - Oh, In-Hwan A1 - Okoro, Anselm A1 - Olusanya, Jacob Olusegun A1 - Olusanya, Bolajoko O A1 - Ortiz, Alberto A1 - Paudel, Deepak A1 - Pereira, David M A1 - Perico, Norberto A1 - Petzold, Max A1 - Phillips, Michael Robert A1 - Polanczyk, Guilherme V A1 - Pourmalek, Farshad A1 - Qorbani, Mostafa A1 - Rafay, Anwar A1 - Rahimi-Movaghar, Vafa A1 - Rahman, Mahfuzar A1 - Rai, Rajesh Kumar A1 - Ram, Usha A1 - Rankin, Zane A1 - Remuzzi, Giuseppe A1 - Renzaho, Andre M N A1 - Roba, Hirbo Shore A1 - Rojas-Rueda, David A1 - Ronfani, Luca A1 - Sagar, Rajesh A1 - Sanabria, Juan Ramon A1 - Kedir Mohammed, Muktar Sano A1 - Santos, Itamar S A1 - Satpathy, Maheswar A1 - Sawhney, Monika A1 - Schöttker, Ben A1 - Schwebel, David C A1 - Scott, James G A1 - Sepanlou, Sadaf G A1 - Shaheen, Amira A1 - Shaikh, Masood Ali A1 - She, June A1 - Shiri, Rahman A1 - Shiue, Ivy A1 - Sigfusdottir, Inga Dora A1 - Singh, Jasvinder A1 - Silpakit, Naris A1 - Smith, Alison A1 - Sreeramareddy, Chandrashekhar A1 - Stanaway, Jeffrey D A1 - Stein, Dan J A1 - Steiner, Caitlyn A1 - Sufiyan, Muawiyyah Babale A1 - Swaminathan, Soumya A1 - Tabarés-Seisdedos, Rafael A1 - Tabb, Karen M A1 - Tadese, Fentaw A1 - Tavakkoli, Mohammad A1 - Taye, Bineyam A1 - Teeple, Stephanie A1 - Tegegne, Teketo Kassaw A1 - Temam Shifa, Girma A1 - Terkawi, Abdullah Sulieman A1 - Thomas, Bernadette A1 - Thomson, Alan J A1 - Tobe-Gai, Ruoyan A1 - Tonelli, Marcello A1 - Tran, Bach Xuan A1 - Troeger, Christopher A1 - Ukwaja, Kingsley N A1 - Uthman, Olalekan A1 - Vasankari, Tommi A1 - Venketasubramanian, Narayanaswamy A1 - Vlassov, Vasiliy Victorovich A1 - Weiderpass, Elisabete A1 - Weintraub, Robert A1 - Gebrehiwot, Solomon Weldemariam A1 - Westerman, Ronny A1 - Williams, Hywel C A1 - Wolfe, Charles D A A1 - Woodbrook, Rachel A1 - Yano, Yuichiro A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa Z A1 - Yu, Chuanhua A1 - Zaki, Maysaa El Sayed A1 - Zegeye, Elias Asfaw A1 - Zuhlke, Liesl Joanna A1 - Murray, Christopher J L A1 - Vos, Theo KW - Adolescent KW - Adolescent Health KW - Age Factors KW - Cause of Death KW - Child KW - Child Health KW - Child Mortality KW - Disabled Children KW - Female KW - Global Burden of Disease KW - Global Health KW - Humans KW - Male KW - Pregnancy KW - Pregnancy Complications KW - Risk Factors KW - Sex Factors KW - Wounds and Injuries AB -

Importance: Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health.

Objective: To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion.

Evidence Review: Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss.

Findings: Global child and adolescent mortality decreased from 14.18 million (95% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75%) in 2015 than was the case in 1990 (61%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3% (95% UI, 3.1%-5.6%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries.

Conclusions and Relevance: Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.

VL - 171 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28384795?dopt=Abstract ER - TY - JOUR T1 - [Clinical and molecular study in a family with autosomal dominant hypohidrotic ectodermal dysplasia]. JF - Arch Argent Pediatr Y1 - 2017 A1 - Callea, Michele A1 - Cammarata-Scalisi, Francisco A1 - Willoughby, Colin E A1 - Giglio, Sabrina R A1 - Sani, Ilaria A1 - Bargiacchi, Sara A1 - Traficante, Giovanna A1 - Bellacchio, Emanuele A1 - Tadini, Gianluca A1 - Yavuz, Izzet A1 - Galeotti, Angela A1 - Clarich, Gabriella KW - Child, Preschool KW - Ectodermal Dysplasia 1, Anhidrotic KW - Edar Receptor KW - Humans KW - Male KW - Mutation KW - Pedigree AB -

Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed.

VL - 115 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28097853?dopt=Abstract ER - TY - JOUR T1 - CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment. JF - Environ Int Y1 - 2017 A1 - Llop, Sabrina A1 - Tran, Van A1 - Ballester, Ferran A1 - Barbone, Fabio A1 - Sofianou-Katsoulis, Aikaterini A1 - Sunyer, Jordi A1 - Engström, Karin A1 - Alhamdow, Ayman A1 - Love, Tanzy M A1 - Watson, Gene E A1 - Bustamante, Mariona A1 - Murcia, Mario A1 - Iñiguez, Carmen A1 - Shamlaye, Conrad F A1 - Rosolen, Valentina A1 - Mariuz, Marika A1 - Horvat, Milena A1 - Tratnik, Janja S A1 - Mazej, Darja A1 - van Wijngaarden, Edwin A1 - Davidson, Philip W A1 - Myers, Gary J A1 - Rand, Matthew D A1 - Broberg, Karin KW - Adult KW - Child Development KW - Child, Preschool KW - Cohort Studies KW - Cytochrome P-450 CYP3A KW - Female KW - Fetal Blood KW - Genotype KW - Greece KW - Humans KW - Infant KW - Italy KW - Male KW - Mercury KW - Methylmercury Compounds KW - Neurodevelopmental Disorders KW - Neuropsychological Tests KW - Polymorphism, Genetic KW - Pregnancy KW - Prenatal Exposure Delayed Effects KW - Seychelles KW - Spain AB -

BACKGROUND: Results on the association between prenatal exposure to methylmercury (MeHg) and child neuropsychological development are heterogeneous. Underlying genetic differences across study populations could contribute to this varied response to MeHg. Studies in Drosophila have identified the cytochrome p450 3A (CYP3A) family as candidate MeHg susceptibility genes.

OBJECTIVES: We evaluated whether genetic variation in CYP3A genes influences the association between prenatal exposure to MeHg and child neuropsychological development.

METHODS: The study population included 2639 children from three birth cohort studies: two subcohorts in Seychelles (SCDS) (n=1160, 20 and 30months of age, studied during the years 2001-2012), two subcohorts from Spain (INMA) (n=625, 14months of age, 2003-2009), and two subcohorts from Italy and Greece (PHIME) (n=854, 18months of age, 2006-2011). Total mercury, as a surrogate of MeHg, was analyzed in maternal hair and/or cord blood samples. Neuropsychological development was evaluated using Bayley Scales of Infant Development (BSID). Three functional polymorphisms in the CYP3A family were analyzed: rs2257401 (CYP3A7), rs776746 (CYP3A5), and rs2740574 (CYP3A4).

RESULTS: There was no association between CYP3A polymorphisms and cord mercury concentrations. The scores for the BSID mental scale improved with increasing cord blood mercury concentrations for carriers of the most active alleles (β[95% CI]:=2.9[1.53,4.27] for CYP3A7 rs2257401 GG+GC, 2.51[1.04,3.98] for CYP3A5 rs776746 AA+AG and 2.31[0.12,4.50] for CYP3A4 rs2740574 GG+AG). This association was near the null for CYP3A7 CC, CYP3A5 GG and CYP3A4 AA genotypes. The interaction between the CYP3A genes and total mercury was significant (p<0.05) in European cohorts only.

CONCLUSIONS: Our results suggest that the polymorphisms in CYP3A genes may modify the response to dietary MeHg exposure during early life development.

VL - 105 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28500872?dopt=Abstract ER - TY - JOUR T1 - Enrichment of low-frequency functional variants revealed by whole-genome sequencing of multiple isolated European populations. JF - Nat Commun Y1 - 2017 A1 - Xue, Yali A1 - Mezzavilla, Massimo A1 - Haber, Marc A1 - McCarthy, Shane A1 - Chen, Yuan A1 - Narasimhan, Vagheesh A1 - Gilly, Arthur A1 - Ayub, Qasim A1 - Colonna, Vincenza A1 - Southam, Lorraine A1 - Finan, Christopher A1 - Massaia, Andrea A1 - Chheda, Himanshu A1 - Palta, Priit A1 - Ritchie, Graham A1 - Asimit, Jennifer A1 - Dedoussis, George A1 - Gasparini, Paolo A1 - Palotie, Aarno A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Wilson, James F A1 - Durbin, Richard A1 - Tyler-Smith, Chris A1 - Zeggini, Eleftheria KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Genetics, Population KW - Genome, Human KW - Humans KW - Polymorphism, Single Nucleotide KW - Whole Genome Sequencing AB -

The genetic features of isolated populations can boost power in complex-trait association studies, and an in-depth understanding of how their genetic variation has been shaped by their demographic history can help leverage these advantageous characteristics. Here, we perform a comprehensive investigation using 3,059 newly generated low-depth whole-genome sequences from eight European isolates and two matched general populations, together with published data from the 1000 Genomes Project and UK10K. Sequencing data give deeper and richer insights into population demography and genetic characteristics than genotype-chip data, distinguishing related populations more effectively and allowing their functional variants to be studied more fully. We demonstrate relaxation of purifying selection in the isolates, leading to enrichment of rare and low-frequency functional variants, using novel statistics, DVxy and SVxy. We also develop an isolation-index (Isx) that predicts the overall level of such key genetic characteristics and can thus help guide population choice in future complex-trait association studies.

VL - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28643794?dopt=Abstract ER - TY - JOUR T1 - Fetal monitoring indications for delivery and 2-year outcome in 310 infants with fetal growth restriction delivered before 32 weeks' gestation in the TRUFFLE study. JF - Ultrasound Obstet Gynecol Y1 - 2017 A1 - Visser, G H A A1 - Bilardo, C M A1 - Derks, J B A1 - Ferrazzi, E A1 - Fratelli, N A1 - Frusca, T A1 - Ganzevoort, W A1 - Lees, C C A1 - Napolitano, R A1 - Todros, T A1 - Wolf, H A1 - Hecher, K KW - Cardiotocography KW - Delivery, Obstetric KW - Female KW - Fetal Growth Retardation KW - Fetal Monitoring KW - Fetus KW - Gestational Age KW - Humans KW - Infant, Newborn KW - Male KW - Netherlands KW - Pregnancy KW - Pregnancy Outcome KW - Pulsatile Flow KW - Survival Analysis KW - Ultrasonography, Prenatal KW - Umbilical Arteries AB -

OBJECTIVE: In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short-term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV-p95); and (3) late changes in fetal DV waveform (DV-no-A). However, many infants per monitoring protocol were delivered because of safety-net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2-year outcome in infants delivered before 32 weeks to further refine management proposals.

METHODS: We included all 310 cases of the TRUFFLE study with known outcome at 2 years' corrected age and seven fetal deaths, excluding seven cases with inevitable perinatal death. Data were analyzed according to the allocated fetal monitoring strategy in combination with the indication for delivery.

RESULTS: Overall, only 32% of liveborn infants were delivered according to the specified monitoring parameter for indication for delivery; 38% were delivered because of safety-net criteria, 15% for other fetal reasons and 15% for maternal reasons. In the CTG-STV group, 51% of infants were delivered because of reduced STV. In the DV-p95 group, 34% of infants were delivered because of abnormal DV and, in the DV-no-A group, only 10% of infants were delivered accordingly. The majority of infants in the DV groups were delivered for the safety-net criterion of spontaneous decelerations in FHR. Two-year intact survival was highest in the DV groups combined compared with the CTG-STV group (P = 0.05 for live births only, P = 0.21 including fetal death), with no difference between DV groups. A poorer outcome in the CTG-STV group was restricted to infants delivered because of FHR decelerations in the safety-net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non-significantly higher intact survival.

CONCLUSIONS: In this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG-STV criteria were used as a safety net but in the CTG-STV group, no DV safety-net criteria were applied, we speculate that the slightly poorer outcome in the CTG-STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

VL - 50 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27854382?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. JF - Nat Genet Y1 - 2017 A1 - Warren, Helen R A1 - Evangelou, Evangelos A1 - Cabrera, Claudia P A1 - Gao, He A1 - Ren, Meixia A1 - Mifsud, Borbala A1 - Ntalla, Ioanna A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Cook, James P A1 - Kraja, Aldi T A1 - Drenos, Fotios A1 - Loh, Marie A1 - Verweij, Niek A1 - Marten, Jonathan A1 - Karaman, Ibrahim A1 - Lepe, Marcelo P Segura A1 - O'Reilly, Paul F A1 - Knight, Joanne A1 - Snieder, Harold A1 - Kato, Norihiro A1 - He, Jiang A1 - Tai, E Shyong A1 - Said, M Abdullah A1 - Porteous, David A1 - Alver, Maris A1 - Poulter, Neil A1 - Farrall, Martin A1 - Gansevoort, Ron T A1 - Padmanabhan, Sandosh A1 - Mägi, Reedik A1 - Stanton, Alice A1 - Connell, John A1 - Bakker, Stephan J L A1 - Metspalu, Andres A1 - Shields, Denis C A1 - Thom, Simon A1 - Brown, Morris A1 - Sever, Peter A1 - Esko, Tõnu A1 - Hayward, Caroline A1 - van der Harst, Pim A1 - Saleheen, Danish A1 - Chowdhury, Rajiv A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Newton-Cheh, Christopher A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Kooner, Jaspal S A1 - Keavney, Bernard A1 - Tomaszewski, Maciej A1 - Samani, Nilesh J A1 - Howson, Joanna M M A1 - Tobin, Martin D A1 - Munroe, Patricia B A1 - Ehret, Georg B A1 - Wain, Louise V KW - Adult KW - Blood Pressure KW - Cardiovascular Diseases KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

VL - 49 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28135244?dopt=Abstract ER - TY - JOUR T1 - Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. JF - Nat Genet Y1 - 2017 A1 - Day, Felix R A1 - Thompson, Deborah J A1 - Helgason, Hannes A1 - Chasman, Daniel I A1 - Finucane, Hilary A1 - Sulem, Patrick A1 - Ruth, Katherine S A1 - Whalen, Sean A1 - Sarkar, Abhishek K A1 - Albrecht, Eva A1 - Altmaier, Elisabeth A1 - Amini, Marzyeh A1 - Barbieri, Caterina M A1 - Boutin, Thibaud A1 - Campbell, Archie A1 - Demerath, Ellen A1 - Giri, Ayush A1 - He, Chunyan A1 - Hottenga, Jouke J A1 - Karlsson, Robert A1 - Kolcic, Ivana A1 - Loh, Po-Ru A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Marco, Brumat A1 - McMahon, George A1 - Medland, Sarah E A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - Nutile, Teresa A1 - Paternoster, Lavinia A1 - Perjakova, Natalia A1 - Porcu, Eleonora A1 - Rose, Lynda M A1 - Schraut, Katharina E A1 - Segrè, Ayellet V A1 - Smith, Albert V A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Andrulis, Irene L A1 - Bandinelli, Stefania A1 - Beckmann, Matthias W A1 - Benitez, Javier A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Brand, Judith S A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Broer, Linda A1 - Brüning, Thomas A1 - Buring, Julie E A1 - Campbell, Harry A1 - Catamo, Eulalia A1 - Chanock, Stephen A1 - Chenevix-Trench, Georgia A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cousminer, Diana L A1 - Cox, Angela A1 - Crisponi, Laura A1 - Czene, Kamila A1 - Davey Smith, George A1 - de Geus, Eco J C N A1 - de Mutsert, Renée A1 - De Vivo, Immaculata A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dos-Santos-Silva, Isabel A1 - Dunning, Alison M A1 - Eriksson, Johan G A1 - Fasching, Peter A A1 - Fernández-Rhodes, Lindsay A1 - Ferrucci, Luigi A1 - Flesch-Janys, Dieter A1 - Franke, Lude A1 - Gabrielson, Marike A1 - Gandin, Ilaria A1 - Giles, Graham G A1 - Grallert, Harald A1 - Gudbjartsson, Daniel F A1 - Guenel, Pascal A1 - Hall, Per A1 - Hallberg, Emily A1 - Hamann, Ute A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Heiss, Gerardo A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank A1 - Hunter, David J A1 - Ikram, M Arfan A1 - Im, Hae Kyung A1 - Järvelin, Marjo-Riitta A1 - Joshi, Peter K A1 - Karasik, David A1 - Kellis, Manolis A1 - Kutalik, Zoltán A1 - LaChance, Genevieve A1 - Lambrechts, Diether A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Lenarduzzi, Stefania A1 - Li, Jingmei A1 - Lind, Penelope A A1 - Lindström, Sara A1 - Liu, Yongmei A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Mannermaa, Arto A1 - Mbarek, Hamdi A1 - McCarthy, Mark I A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Metspalu, Andres A1 - Michailidou, Kyriaki A1 - Milani, Lili A1 - Milne, Roger L A1 - Montgomery, Grant W A1 - Mulligan, Anna M A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nevanlinna, Heli A1 - Nyholt, Dale R A1 - Oldehinkel, Albertine J A1 - O'Mara, Tracy A A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Pouta, Anneli A1 - Radice, Paolo A1 - Rahman, Iffat A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Schmidt, Marjanka K A1 - Scott, Robert A A1 - Shah, Mitul A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Sovio, Ulla A1 - Stampfer, Meir A1 - Steri, Maristella A1 - Strauch, Konstantin A1 - Tanaka, Toshiko A1 - Tikkanen, Emmi A1 - Timpson, Nicholas J A1 - Traglia, Michela A1 - Truong, Therese A1 - Tyrer, Jonathan P A1 - Uitterlinden, André G A1 - Edwards, Digna R Velez A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wang, Qin A1 - Widen, Elisabeth A1 - van Dijk, Ko Willems A1 - Willemsen, Gonneke A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Jing Hua A1 - Zoledziewska, Magdalena A1 - Zygmunt, Marek A1 - Alizadeh, Behrooz Z A1 - Boomsma, Dorret I A1 - Ciullo, Marina A1 - Cucca, Francesco A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Kraft, Peter A1 - Lawlor, Debbie A A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Mook-Kanamori, Dennis O A1 - Nohr, Ellen A A1 - Polasek, Ozren A1 - Porteous, David A1 - Price, Alkes L A1 - Ridker, Paul M A1 - Snieder, Harold A1 - Spector, Tim D A1 - Stöckl, Doris A1 - Toniolo, Daniela A1 - Ulivi, Sheila A1 - Visser, Jenny A A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Wilson, James F A1 - Spurdle, Amanda B A1 - Thorsteindottir, Unnur A1 - Pollard, Katherine S A1 - Easton, Douglas F A1 - Tung, Joyce Y A1 - Chang-Claude, Jenny A1 - Hinds, David A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Stefansson, Kari A1 - Ong, Ken K A1 - Perry, John R B KW - Adolescent KW - Age Factors KW - Body Mass Index KW - Databases, Genetic KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomic Imprinting KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Menarche KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Puberty KW - Quantitative Trait Loci KW - Ribonucleoproteins KW - Risk Factors AB -

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

VL - 49 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28436984?dopt=Abstract ER - TY - JOUR T1 - How to monitor pregnancies complicated by fetal growth restriction and delivery before 32 weeks: post-hoc analysis of TRUFFLE study. JF - Ultrasound Obstet Gynecol Y1 - 2017 A1 - Ganzevoort, W A1 - Mensing Van Charante, N A1 - Thilaganathan, B A1 - Prefumo, F A1 - Arabin, B A1 - Bilardo, C M A1 - Brezinka, C A1 - Derks, J B A1 - Diemert, A A1 - Duvekot, J J A1 - Ferrazzi, E A1 - Frusca, T A1 - Hecher, K A1 - Marlow, N A1 - Martinelli, P A1 - Ostermayer, E A1 - Papageorghiou, A T A1 - Schlembach, D A1 - Schneider, K T M A1 - Todros, T A1 - Valcamonico, A A1 - Visser, G H A A1 - Van Wassenaer-Leemhuis, A A1 - Lees, C C A1 - Wolf, H KW - Adult KW - Cardiotocography KW - Central Nervous System Diseases KW - Child, Preschool KW - Female KW - Fetal Growth Retardation KW - Fetal Membranes, Premature Rupture KW - Gestational Age KW - Heart Rate, Fetal KW - Humans KW - Infant KW - Infant, Extremely Premature KW - Male KW - Middle Cerebral Artery KW - Pregnancy KW - Pulsatile Flow KW - Survival Analysis KW - Treatment Outcome KW - Ultrasonography, Prenatal KW - Uterine Artery AB -

OBJECTIVES: In the recent TRUFFLE study, it appeared that, in pregnancies complicated by fetal growth restriction (FGR) between 26 and 32 weeks' gestation, monitoring of the fetal ductus venosus (DV) waveform combined with computed cardiotocography (CTG) to determine timing of delivery increased the chance of infant survival without neurological impairment. However, concerns with the interpretation were raised, as DV monitoring appeared to be associated with a non-significant increase in fetal death, and some infants were delivered after 32 weeks, at which time the study protocol no longer applied. This secondary sensitivity analysis of the TRUFFLE study focuses on women who delivered before 32 completed weeks' gestation and analyzes in detail the cases of fetal death.

METHODS: Monitoring data of 317 pregnancies with FGR that delivered before 32 weeks were analyzed, excluding those with absent outcome data or inevitable perinatal death. Women were allocated randomly to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate short-term variation (STV) on CTG; (2) early changes in fetal DV waveform; and (3) late changes in fetal DV waveform. Primary outcome was 2-year survival without neurological impairment. The association of the last monitoring data before delivery and infant outcome was assessed by multivariable analysis.

RESULTS: Two-year survival without neurological impairment occurred more often in the two DV groups (both 83%) than in the CTG-STV group (77%), however, the difference was not statistically significant (P = 0.21). Among the surviving infants in the DV groups, 93% were free of neurological impairment vs 85% of surviving infants in the CTG-STV group (P = 0.049). All fetal deaths (n = 7) occurred in the groups with DV monitoring. Of the monitoring parameters obtained shortly before fetal death in these seven cases, an abnormal CTG was observed in only one case. Multivariable regression analysis of factors at study entry demonstrated that a later gestational age, higher estimated fetal weight-to-50 percentile ratio and lower umbilical artery pulsatility index (PI)/fetal middle cerebral artery-PI ratio were significantly associated with normal outcome. Allocation to DV monitoring had a smaller effect on outcome, but remained in the model (P < 0.1). Abnormal fetal arterial Doppler before delivery was significantly associated with adverse outcome in the CTG-STV group. In contrast, abnormal DV flow was the only monitoring parameter associated with adverse outcome in the DV groups, while fetal arterial Doppler, STV below the cut-off used in the CTG-STV group and recurrent decelerations in fetal heart rate were not.

CONCLUSIONS: In accordance with the findings of the TRUFFLE study on monitoring and intervention management of very preterm FGR, we found that the proportion of infants surviving without neuroimpairment was not significantly different when the decision for delivery was based on changes in DV waveform vs reduced STV on CTG. The uneven distribution of fetal deaths towards the DV groups was probably a chance effect, and neurological outcome was better among surviving children in these groups. Before 32 weeks, delaying delivery until abnormalities in DV-PI or STV and/or recurrent decelerations in fetal heat rate occur, as defined by the study protocol, is likely to be safe and possibly benefits long-term outcome. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

VL - 49 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28182335?dopt=Abstract ER - TY - JOUR T1 - Improving the quality of hospital care for children by supportive supervision: a cluster randomized trial, Kyrgyzstan. JF - Bull World Health Organ Y1 - 2017 A1 - Lazzerini, Marzia A1 - Shukurova, Venera A1 - Davletbaeva, Marina A1 - Monolbaev, Kubanychbek A1 - Kulichenko, Tatiana A1 - Akoev, Yuri A1 - Bakradze, Maya A1 - Margieva, Tea A1 - Mityushino, Ilya A1 - Namazova-Baranova, Leyla A1 - Boronbayeva, Elnura A1 - Kuttumuratova, Aigul A1 - Weber, Martin Willy A1 - Tamburlini, Giorgio KW - Child KW - Child Care KW - Cluster Analysis KW - Hospitalization KW - Hospitals, Public KW - Humans KW - Kyrgyzstan KW - Medical Audit KW - Pediatricians KW - Professional Role KW - Prospective Studies KW - Quality Improvement AB -

OBJECTIVE: To determine whether periodic supportive supervision after a training course improved the quality of paediatric hospital care in Kyrgyzstan, where inappropriate care was common but in-hospital postnatal mortality was low.

METHODS: In a cluster, randomized, parallel-group trial, 10 public hospitals were allocated to a 4-day World Health Organization (WHO) course on hospital care for children followed by periodic supportive supervision by paediatricians for 1 year, while 10 hospitals had no intervention. We assessed prospectively 10 key indicators of inappropriate paediatric case management, as indicated by WHO guidelines. The primary indicator was the combination of the three indicators: unnecessary hospitalization, increased iatrogenic risk and unnecessary painful procedures. An independent team evaluated the overall quality of care.

FINDINGS: We prospectively reviewed the medical records of 4626 hospitalized children aged 2 to 60 months. In the intervention hospitals, the mean proportion of the primary indicator decreased from 46.9% (95% confidence interval, CI: 24.2 to 68.9) at baseline to 6.8% (95% CI: 1.1 to 12.1) at 1 year, but was unchanged in the control group (45.5%, 95% CI: 25.2 to 67.9, to 64.7%, 95% CI: 43.3 to 86.1). At 1 year, the risk ratio for the primary indicator in the intervention versus the control group was 0.09 (95% CI: 0.06 to 0.13). The proportions of the other nine indicators also decreased in the intervention group ( < 0.0001 for all). Overall quality of care improved significantly in intervention hospitals.

CONCLUSION: Periodic supportive supervision for 1 year after a training course improved both adherence to WHO guidelines on hospital care for children and the overall quality of paediatric care.

VL - 95 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28603306?dopt=Abstract ER - TY - JOUR T1 - ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development. JF - Sci Rep Y1 - 2017 A1 - Zhang, Rong A1 - Knapp, Michael A1 - Suzuki, Kentaro A1 - Kajioka, Daiki A1 - Schmidt, Johanna M A1 - Winkler, Jonas A1 - Yilmaz, Öznur A1 - Pleschka, Michael A1 - Cao, Jia A1 - Kockum, Christina Clementson A1 - Barker, Gillian A1 - Holmdahl, Gundela A1 - Beaman, Glenda A1 - Keene, David A1 - Woolf, Adrian S A1 - Cervellione, Raimondo M A1 - Cheng, Wei A1 - Wilkins, Simon A1 - Gearhart, John P A1 - Sirchia, Fabio A1 - Di Grazia, Massimo A1 - Ebert, Anne-Karolin A1 - Rösch, Wolfgang A1 - Ellinger, Jörg A1 - Jenetzky, Ekkehart A1 - Zwink, Nadine A1 - Feitz, Wout F A1 - Marcelis, Carlo A1 - Schumacher, Johannes A1 - Martinón-Torres, Federico A1 - Hibberd, Martin Lloyd A1 - Khor, Chiea Chuen A1 - Heilmann-Heimbach, Stefanie A1 - Barth, Sandra A1 - Boyadjiev, Simeon A A1 - Brusco, Alfredo A1 - Ludwig, Michael A1 - Newman, William A1 - Nordenskjöld, Agneta A1 - Yamada, Gen A1 - Odermatt, Benjamin A1 - Reutter, Heiko KW - Animals KW - Bladder Exstrophy KW - Embryo, Mammalian KW - Female KW - Gene Expression Regulation, Developmental KW - Genetic Predisposition to Disease KW - Humans KW - Larva KW - LIM-Homeodomain Proteins KW - Mesoderm KW - Mice KW - Organogenesis KW - Polymorphism, Single Nucleotide KW - Pronephros KW - Protein Isoforms KW - Transcription Factors KW - Urinary Tract KW - Zebrafish AB -

Previously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10). A meta-analysis of rs6874700 of our previous and present study showed a p value of 9.2 × 10. Developmental biology models were used to clarify the location of ISL1 activity in the forming urinary tract. Genetic lineage analysis of Isl1-expressing cells by the lineage tracer mouse model showed Isl1-expressing cells in the urinary tract of mouse embryos at E10.5 and distributed in the bladder at E15.5. Expression of isl1 in zebrafish larvae staged 48 hpf was detected in a small region of the developing pronephros. Our study supports ISL1 as a major susceptibility gene for CBE and as a regulator of urinary tract development.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28176844?dopt=Abstract ER - TY - JOUR T1 - Longitudinal study of computerized cardiotocography in early fetal growth restriction. JF - Ultrasound Obstet Gynecol Y1 - 2017 A1 - Wolf, H A1 - Arabin, B A1 - Lees, C C A1 - Oepkes, D A1 - Prefumo, F A1 - Thilaganathan, B A1 - Todros, T A1 - Visser, G H A A1 - Bilardo, C M A1 - Derks, J B A1 - Diemert, A A1 - Duvekot, J J A1 - Ferrazzi, E A1 - Frusca, T A1 - Hecher, K A1 - Marlow, N A1 - Martinelli, P A1 - Ostermayer, E A1 - Papageorghiou, A T A1 - Scheepers, H C J A1 - Schlembach, D A1 - Schneider, K T M A1 - Valcamonico, A A1 - Van Wassenaer-Leemhuis, A A1 - Ganzevoort, W KW - Adult KW - Cardiotocography KW - Child, Preschool KW - Female KW - Fetal Growth Retardation KW - Fetal Heart KW - Heart Rate, Fetal KW - Humans KW - Infant KW - Infant, Newborn KW - Longitudinal Studies KW - Middle Cerebral Artery KW - Pregnancy KW - Pregnancy Outcome KW - Pulsatile Flow KW - Survival Analysis KW - Ultrasonography, Prenatal AB -

OBJECTIVES: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome.

METHODS: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome.

RESULTS: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes.

CONCLUSION: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

VL - 50 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27484356?dopt=Abstract ER - TY - JOUR T1 - MCM8 and MCM9 Nucleotide Variants in Women With Primary Ovarian Insufficiency. JF - J Clin Endocrinol Metab Y1 - 2017 A1 - Desai, Swapna A1 - Wood-Trageser, Michelle A1 - Matic, Jelena A1 - Chipkin, Jaqueline A1 - Jiang, Huaiyang A1 - Bachelot, Anne A1 - Dulon, Jerome A1 - Sala, Cinzia A1 - Barbieri, Caterina A1 - Cocca, Massimiliano A1 - Toniolo, Daniela A1 - Touraine, Philippe A1 - Witchel, Selma A1 - Rajkovic, Aleksandar KW - Adult KW - Aging KW - DNA Damage KW - DNA Repair KW - Female KW - Humans KW - Minichromosome Maintenance Proteins KW - Primary Ovarian Insufficiency KW - Sequence Analysis, DNA AB -

Objective: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI).

Design: MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants.

Setting: Academic research institution.

Participants: All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels.

Interventions: None.

Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging.

Results: MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway.

Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.

VL - 102 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27802094?dopt=Abstract ER - TY - JOUR T1 - Is middle cerebral artery Doppler related to neonatal and 2-year infant outcome in early fetal growth restriction? JF - Am J Obstet Gynecol Y1 - 2017 A1 - Stampalija, Tamara A1 - Arabin, Birgit A1 - Wolf, Hans A1 - Bilardo, Caterina M A1 - Lees, Christoph KW - Birth Weight KW - Child Development KW - Child, Preschool KW - Delivery, Obstetric KW - Female KW - Fetal Growth Retardation KW - Gestational Age KW - Humans KW - Middle Cerebral Artery KW - Pregnancy KW - Prospective Studies KW - Pulsatile Flow KW - Ultrasonography, Doppler KW - Ultrasonography, Prenatal KW - Umbilical Arteries AB -

BACKGROUND: Reduced fetal middle cerebral artery Doppler impedance is associated with hypoxemia in fetal growth restriction. It remains unclear as to whether this finding could be useful in timing delivery, especially in the third trimester. In this regard there is a paucity of evidence from prospective studies.

OBJECTIVES: The aim of this study was to determine whether there is an association between middle cerebral artery Doppler impedance and its ratio with the umbilical artery in relation to neonatal and 2 year infant outcome in early fetal growth restriction (26-31 weeks of gestation). Additionally we sought to explore which ratio is more informative for clinical use.

STUDY DESIGN: This is a secondary analysis from the Trial of Randomized Umbilical and Fetal Flow in Europe, a prospective, multicenter, randomized management study on different antenatal monitoring strategies (ductus venosus Doppler changes and computerized cardiotocography short-term variation) in fetal growth restriction diagnosed between 26 and 31 weeks. We analyzed women with middle cerebral artery Doppler measurement at study entry and within 1 week before delivery and with complete postnatal follow-up (374 of 503). The primary outcome was survival without neurodevelopmental impairment at 2 years corrected for prematurity. Neonatal outcome was defined as survival until first discharge home without severe neonatal morbidity. Z-scores were calculated for middle cerebral artery pulsatility index and both umbilicocerebral and cerebroplacental ratios. Odds ratios of Doppler parameter Z-scores for neonatal and 2 year infant outcome were calculated by multivariable logistic regression analysis adjusted for gestational age and birthweight p50 ratio.

RESULTS: Higher middle cerebral artery pulsatility index at inclusion but not within 1 week before delivery was associated with neonatal survival without severe morbidity (odds ratio, 1.24; 95% confidence interval, 1.02-1.52). Middle cerebral artery pulsatility index Z-score and umbilicocerebral ratio Z-score at inclusion were associated with 2 year survival with normal neurodevelopmental outcome (odds ratio, 1.33; 95% confidence interval, 1.03-1.72, and odds ratio, 0.88; 95% confidence interval, 0.78-0.99, respectively) as were gestation at delivery and birthweight p50 ratio (odds ratio, 1.41; 95% confidence interval, 1.20-1.66, and odds ratio, 1.86; 95% confidence interval, 1.33-2.60, respectively). When comparing cerebroplacental ratio against umbilicocerebral ratio, the incremental range of the cerebroplacental ratio tended toward zero, whereas the umbilicocerebral ratio tended toward infinity as the values became more abnormal.

CONCLUSION: In a monitoring protocol based on ductus venosus and cardiotocography in early fetal growth restriction (26-31 weeks of gestation), the impact of middle cerebral artery Doppler and its ratios on outcome is modest and less marked than birthweight and delivery gestation. It is unlikely that middle cerebral artery Doppler and its ratios are informative in optimizing the timing of delivery in fetal growth restriction before 32 weeks of gestation. The umbilicocerebral ratio allows for a better differentiation in the abnormal range than the cerebroplacental ratio.

VL - 216 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28087423?dopt=Abstract ER - TY - JOUR T1 - Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. JF - Hypertension Y1 - 2017 A1 - Wain, Louise V A1 - Vaez, Ahmad A1 - Jansen, Rick A1 - Joehanes, Roby A1 - van der Most, Peter J A1 - Erzurumluoglu, A Mesut A1 - O'Reilly, Paul F A1 - Cabrera, Claudia P A1 - Warren, Helen R A1 - Rose, Lynda M A1 - Verwoert, Germaine C A1 - Hottenga, Jouke-Jan A1 - Strawbridge, Rona J A1 - Esko, Tõnu A1 - Arking, Dan E A1 - Hwang, Shih-Jen A1 - Guo, Xiuqing A1 - Kutalik, Zoltán A1 - Trompet, Stella A1 - Shrine, Nick A1 - Teumer, Alexander A1 - Ried, Janina S A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Amin, Najaf A1 - Nolte, Ilja M A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Wareham, Nicholas J A1 - Hofer, Edith A1 - Joshi, Peter K A1 - Kristiansson, Kati A1 - Traglia, Michela A1 - Havulinna, Aki S A1 - Goel, Anuj A1 - Nalls, Mike A A1 - Sõber, Siim A1 - Vuckovic, Dragana A1 - Luan, Jian'an A1 - del Greco M, Fabiola A1 - Ayers, Kristin L A1 - Marrugat, Jaume A1 - Ruggiero, Daniela A1 - Lopez, Lorna M A1 - Niiranen, Teemu A1 - Enroth, Stefan A1 - Jackson, Anne U A1 - Nelson, Christopher P A1 - Huffman, Jennifer E A1 - Zhang, Weihua A1 - Marten, Jonathan A1 - Gandin, Ilaria A1 - Harris, Sarah E A1 - Zemunik, Tatijana A1 - Lu, Yingchang A1 - Evangelou, Evangelos A1 - Shah, Nabi A1 - de Borst, Martin H A1 - Mangino, Massimo A1 - Prins, Bram P A1 - Campbell, Archie A1 - Li-Gao, Ruifang A1 - Chauhan, Ganesh A1 - Oldmeadow, Christopher A1 - Abecasis, Goncalo A1 - Abedi, Maryam A1 - Barbieri, Caterina M A1 - Barnes, Michael R A1 - Batini, Chiara A1 - Beilby, John A1 - Blake, Tineka A1 - Boehnke, Michael A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brown, Morris A1 - Brumat, Marco A1 - Campbell, Harry A1 - Chambers, John C A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Connell, John A1 - Cordell, Heather J A1 - Damman, Jeffrey J A1 - Davies, Gail A1 - de Geus, Eco J A1 - de Mutsert, Renée A1 - Deelen, Joris A1 - Demirkale, Yusuf A1 - Doney, Alex S F A1 - Dörr, Marcus A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Gao, He A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Gow, Alan J A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Hui, Jennie A1 - Järvelin, Marjo-Riitta A1 - Johansson, Åsa A1 - Johnson, Andrew D A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Khaw, Kay-Tee A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Langenberg, Claudia A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Mach, François A1 - Mamasoula, Chrysovalanto A1 - Menni, Cristina A1 - Mifsud, Borbala A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nandakumar, Priyanka A1 - Nguyen, Quang Tri A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Saba, Yasaman A1 - Saint Pierre, Aude A1 - Sala, Cinzia F A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Scott, Rodney A1 - Seelen, Marc A A1 - Shields, Denis C A1 - Siscovick, David A1 - Sorice, Rossella A1 - Stanton, Alice A1 - Stott, David J A1 - Sundström, Johan A1 - Swertz, Morris A1 - Taylor, Kent D A1 - Thom, Simon A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Wright, Alan F A1 - Yao, Jie A1 - Thériault, Sébastien A1 - Conen, David A1 - Attia, John A1 - Sever, Peter A1 - Debette, Stéphanie A1 - Mook-Kanamori, Dennis O A1 - Zeggini, Eleftheria A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Palmer, Colin N A A1 - Vergnaud, Anne-Claire A1 - Loos, Ruth J F A1 - Polasek, Ozren A1 - Starr, John M A1 - Girotto, Giorgia A1 - Hayward, Caroline A1 - Kooner, Jaspal S A1 - Lindgren, Cecila M A1 - Vitart, Veronique A1 - Samani, Nilesh J A1 - Tuomilehto, Jaakko A1 - Gyllensten, Ulf A1 - Knekt, Paul A1 - Deary, Ian J A1 - Ciullo, Marina A1 - Elosua, Roberto A1 - Keavney, Bernard D A1 - Hicks, Andrew A A1 - Scott, Robert A A1 - Gasparini, Paolo A1 - Laan, Maris A1 - Liu, Yongmei A1 - Watkins, Hugh A1 - Hartman, Catharina A A1 - Salomaa, Veikko A1 - Toniolo, Daniela A1 - Perola, Markus A1 - Wilson, James F A1 - Schmidt, Helena A1 - Zhao, Jing Hua A1 - Lehtimäki, Terho A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Rettig, Rainer A1 - James, Alan A1 - Jukema, J Wouter A1 - Strachan, David P A1 - Palmas, Walter A1 - Metspalu, Andres A1 - Ingelsson, Erik A1 - Boomsma, Dorret I A1 - Franco, Oscar H A1 - Bochud, Murielle A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Elliott, Paul A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Knight, Joanne A1 - Morris, Andrew P A1 - Levy, Daniel A1 - Tobin, Martin D A1 - Snieder, Harold A1 - Caulfield, Mark J A1 - Ehret, Georg B AB -

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near , , , , , and , and provide new replication evidence for a further 2 signals in and Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/28739976?dopt=Abstract ER - TY - JOUR T1 - Rare and low-frequency coding variants alter human adult height. JF - Nature Y1 - 2017 A1 - Marouli, Eirini A1 - Graff, Mariaelisa A1 - Medina-Gomez, Carolina A1 - Lo, Ken Sin A1 - Wood, Andrew R A1 - Kjaer, Troels R A1 - Fine, Rebecca S A1 - Lu, Yingchang A1 - Schurmann, Claudia A1 - Highland, Heather M A1 - Rüeger, Sina A1 - Thorleifsson, Gudmar A1 - Justice, Anne E A1 - Lamparter, David A1 - Stirrups, Kathleen E A1 - Turcot, Valérie A1 - Young, Kristin L A1 - Winkler, Thomas W A1 - Esko, Tõnu A1 - Karaderi, Tugce A1 - Locke, Adam E A1 - Masca, Nicholas G D A1 - Ng, Maggie C Y A1 - Mudgal, Poorva A1 - Rivas, Manuel A A1 - Vedantam, Sailaja A1 - Mahajan, Anubha A1 - Guo, Xiuqing A1 - Abecasis, Goncalo A1 - Aben, Katja K A1 - Adair, Linda S A1 - Alam, Dewan S A1 - Albrecht, Eva A1 - Allin, Kristine H A1 - Allison, Matthew A1 - Amouyel, Philippe A1 - Appel, Emil V A1 - Arveiler, Dominique A1 - Asselbergs, Folkert W A1 - Auer, Paul L A1 - Balkau, Beverley A1 - Banas, Bernhard A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bergmann, Sven A1 - Bielak, Lawrence F A1 - Blüher, Matthias A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Böger, Carsten A A1 - Bonnycastle, Lori L A1 - Bork-Jensen, Jette A1 - Bots, Michiel L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Brandslund, Ivan A1 - Breen, Gerome A1 - Brilliant, Murray H A1 - Broer, Linda A1 - Burt, Amber A A1 - Butterworth, Adam S A1 - Carey, David J A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Cook, James P A1 - Corley, Janie A1 - Galbany, Jordi Corominas A1 - Cox, Amanda J A1 - Cuellar-Partida, Gabriel A1 - Danesh, John A1 - Davies, Gail A1 - de Bakker, Paul I W A1 - de Borst, Gert J A1 - de Denus, Simon A1 - de Groot, Mark C H A1 - de Mutsert, Renée A1 - Deary, Ian J A1 - Dedoussis, George A1 - Demerath, Ellen W A1 - den Hollander, Anneke I A1 - Dennis, Joe G A1 - Di Angelantonio, Emanuele A1 - Drenos, Fotios A1 - Du, Mengmeng A1 - Dunning, Alison M A1 - Easton, Douglas F A1 - Ebeling, Tapani A1 - Edwards, Todd L A1 - Ellinor, Patrick T A1 - Elliott, Paul A1 - Evangelou, Evangelos A1 - Farmaki, Aliki-Eleni A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Feng, Shuang A1 - Ferrannini, Ele A1 - Ferrario, Marco M A1 - Ferrières, Jean A1 - Florez, Jose C A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frikke-Schmidt, Ruth A1 - Galesloot, Tessel E A1 - Gan, Wei A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Giri, Ayush A1 - Girotto, Giorgia A1 - Gordon, Scott D A1 - Gordon-Larsen, Penny A1 - Gorski, Mathias A1 - Grarup, Niels A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Hansen, Torben A1 - Harris, Kathleen Mullan A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - He, Liang A1 - Heid, Iris M A1 - Heikkilä, Kauko A1 - Helgeland, Øyvind A1 - Hernesniemi, Jussi A1 - Hewitt, Alex W A1 - Hocking, Lynne J A1 - Hollensted, Mette A1 - Holmen, Oddgeir L A1 - Hovingh, G Kees A1 - Howson, Joanna M M A1 - Hoyng, Carel B A1 - Huang, Paul L A1 - Hveem, Kristian A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Jackson, Anne U A1 - Jansson, Jan-Håkan A1 - Jarvik, Gail P A1 - Jensen, Gorm B A1 - Jhun, Min A A1 - Jia, Yucheng A1 - Jiang, Xuejuan A1 - Johansson, Stefan A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kahali, Bratati A1 - Kahn, René S A1 - Kähönen, Mika A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Kaprio, Jaakko A1 - Karaleftheri, Maria A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Keeman, Renske A1 - Kiemeney, Lambertus A A1 - Kitajima, Hidetoshi A1 - Kluivers, Kirsten B A1 - Kocher, Thomas A1 - Komulainen, Pirjo A1 - Kontto, Jukka A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kuivaniemi, Helena A1 - Küry, Sébastien A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Larson, Eric B A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Lewis, Cora E A1 - Li, Huaixing A1 - Li, Jin A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Lin, Li-An A1 - Lin, Xu A1 - Lind, Lars A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Liu, Yeheng A1 - Liu, Yongmei A1 - Lophatananon, Artitaya A1 - Luan, Jian'an A1 - Lubitz, Steven A A1 - Lyytikäinen, Leo-Pekka A1 - Mackey, David A A1 - Madden, Pamela A F A1 - Manning, Alisa K A1 - Männistö, Satu A1 - Marenne, Gaëlle A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mazul, Angela L A1 - Meidtner, Karina A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Nikus, Kjell A1 - Njølstad, Pål R A1 - Nordestgaard, Børge G A1 - Ntalla, Ioanna A1 - O'Connel, Jeffrey R A1 - Oksa, Heikki A1 - Loohuis, Loes M Olde A1 - Ophoff, Roel A A1 - Owen, Katharine R A1 - Packard, Chris J A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasterkamp, Gerard A1 - Patel, Aniruddh P A1 - Pattie, Alison A1 - Pedersen, Oluf A1 - Peissig, Peggy L A1 - Peloso, Gina M A1 - Pennell, Craig E A1 - Perola, Markus A1 - Perry, James A A1 - Perry, John R B A1 - Person, Thomas N A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Raitakari, Olli T A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil A1 - Robino, Antonietta A1 - Rolandsson, Olov A1 - Rudan, Igor A1 - Ruth, Katherine S A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sandow, Kevin A1 - Sapkota, Yadav A1 - Sattar, Naveed A1 - Schmidt, Marjanka K A1 - Schreiner, Pamela J A1 - Schulze, Matthias B A1 - Scott, Robert A A1 - Segura-Lepe, Marcelo P A1 - Shah, Svati A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert Vernon A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Surendran, Praveen A1 - 't Hart, Leen M A1 - Tansey, Katherine E A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Thorsteinsdottir, Unnur A1 - Thuesen, Betina H A1 - Tönjes, Anke A1 - Tromp, Gerard A1 - Trompet, Stella A1 - Tsafantakis, Emmanouil A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - Tyrer, Jonathan P A1 - Uher, Rudolf A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - van der Laan, Sander W A1 - Van Der Leij, Andries R A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - van Setten, Jessica A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Varma, Rohit A1 - Edwards, Digna R Velez A1 - Vermeulen, Sita H A1 - Vestergaard, Henrik A1 - Vitart, Veronique A1 - Vogt, Thomas F A1 - Vozzi, Diego A1 - Walker, Mark A1 - Wang, Feijie A1 - Wang, Carol A A1 - Wang, Shuai A1 - Wang, Yiqin A1 - Wareham, Nicholas J A1 - Warren, Helen R A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Wilson, James G A1 - Witte, Daniel R A1 - Woods, Michael O A1 - Wu, Ying A1 - Yaghootkar, Hanieh A1 - Yao, Jie A1 - Yao, Pang A1 - Yerges-Armstrong, Laura M A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhan, Xiaowei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zhao, Wei A1 - Zheng, He A1 - Zhou, Wei A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - Kathiresan, Sekar A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Stefansson, Kari A1 - Borecki, Ingrid B A1 - Liu, Dajiang J A1 - North, Kari E A1 - Heard-Costa, Nancy L A1 - Pers, Tune H A1 - Lindgren, Cecilia M A1 - Oxvig, Claus A1 - Kutalik, Zoltán A1 - Rivadeneira, Fernando A1 - Loos, Ruth J F A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Deloukas, Panos A1 - Lettre, Guillaume KW - ADAMTS Proteins KW - Adult KW - Alleles KW - Body Height KW - Cell Adhesion Molecules KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome, Human KW - Glycoproteins KW - Glycosaminoglycans KW - Hedgehog Proteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Interferon Regulatory Factors KW - Interleukin-11 Receptor alpha Subunit KW - Male KW - Multifactorial Inheritance KW - NADPH Oxidase 4 KW - NADPH Oxidases KW - Phenotype KW - Pregnancy-Associated Plasma Protein-A KW - Procollagen N-Endopeptidase KW - Proteoglycans KW - Proteolysis KW - Receptors, Androgen KW - Somatomedins AB -

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

VL - 542 IS - 7640 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract ER - TY - JOUR T1 - Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits. JF - Am J Hum Genet Y1 - 2017 A1 - Tachmazidou, Ioanna A1 - Süveges, Dániel A1 - Min, Josine L A1 - Ritchie, Graham R S A1 - Steinberg, Julia A1 - Walter, Klaudia A1 - Iotchkova, Valentina A1 - Schwartzentruber, Jeremy A1 - Huang, Jie A1 - Memari, Yasin A1 - McCarthy, Shane A1 - Crawford, Andrew A A1 - Bombieri, Cristina A1 - Cocca, Massimiliano A1 - Farmaki, Aliki-Eleni A1 - Gaunt, Tom R A1 - Jousilahti, Pekka A1 - Kooijman, Marjolein N A1 - Lehne, Benjamin A1 - Malerba, Giovanni A1 - Männistö, Satu A1 - Matchan, Angela A1 - Medina-Gomez, Carolina A1 - Metrustry, Sarah J A1 - Nag, Abhishek A1 - Ntalla, Ioanna A1 - Paternoster, Lavinia A1 - Rayner, Nigel W A1 - Sala, Cinzia A1 - Scott, William R A1 - Shihab, Hashem A A1 - Southam, Lorraine A1 - St Pourcain, Beate A1 - Traglia, Michela A1 - Trajanoska, Katerina A1 - Zaza, Gialuigi A1 - Zhang, Weihua A1 - Artigas, María S A1 - Bansal, Narinder A1 - Benn, Marianne A1 - Chen, Zhongsheng A1 - Danecek, Petr A1 - Lin, Wei-Yu A1 - Locke, Adam A1 - Luan, Jian'an A1 - Manning, Alisa K A1 - Mulas, Antonella A1 - Sidore, Carlo A1 - Tybjaerg-Hansen, Anne A1 - Varbo, Anette A1 - Zoledziewska, Magdalena A1 - Finan, Chris A1 - Hatzikotoulas, Konstantinos A1 - Hendricks, Audrey E A1 - Kemp, John P A1 - Moayyeri, Alireza A1 - Panoutsopoulou, Kalliope A1 - Szpak, Michal A1 - Wilson, Scott G A1 - Boehnke, Michael A1 - Cucca, Francesco A1 - Di Angelantonio, Emanuele A1 - Langenberg, Claudia A1 - Lindgren, Cecilia A1 - McCarthy, Mark I A1 - Morris, Andrew P A1 - Nordestgaard, Børge G A1 - Scott, Robert A A1 - Tobin, Martin D A1 - Wareham, Nicholas J A1 - Burton, Paul A1 - Chambers, John C A1 - Smith, George Davey A1 - Dedoussis, George A1 - Felix, Janine F A1 - Franco, Oscar H A1 - Gambaro, Giovanni A1 - Gasparini, Paolo A1 - Hammond, Christopher J A1 - Hofman, Albert A1 - Jaddoe, Vincent W V A1 - Kleber, Marcus A1 - Kooner, Jaspal S A1 - Perola, Markus A1 - Relton, Caroline A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Salomaa, Veikko A1 - Spector, Timothy D A1 - Stegle, Oliver A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Barroso, Inês A1 - Greenwood, Celia M T A1 - Perry, John R B A1 - Walker, Brian R A1 - Butterworth, Adam S A1 - Xue, Yali A1 - Durbin, Richard A1 - Small, Kerrin S A1 - Soranzo, Nicole A1 - Timpson, Nicholas J A1 - Zeggini, Eleftheria KW - Anthropometry KW - Body Height KW - Cohort Studies KW - Databases, Genetic KW - DNA Methylation KW - Female KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lipodystrophy KW - Male KW - Meta-Analysis as Topic KW - Obesity KW - Physical Chromosome Mapping KW - Quantitative Trait Loci KW - Sequence Analysis, DNA KW - Sex Characteristics KW - Syndrome KW - United Kingdom AB -

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.

VL - 100 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28552196?dopt=Abstract ER - TY - JOUR T1 - Withdrawal Assessment Tool-1 Monitoring in PICU: A Multicenter Study on Iatrogenic Withdrawal Syndrome. JF - Pediatr Crit Care Med Y1 - 2017 A1 - Amigoni, Angela A1 - Mondardini, Maria Cristina A1 - Vittadello, Ilaria A1 - Zaglia, Federico A1 - Rossetti, Emanuele A1 - Vitale, Francesca A1 - Ferrario, Stefania A1 - Savron, Fabio A1 - Coffaro, Giancarlo A1 - Brugnaro, Luca A1 - Amato, Roberta A1 - Wolfler, Andrea A1 - Franck, Linda S KW - Adolescent KW - Analgesics KW - Child KW - Child, Preschool KW - Critical Care KW - Female KW - Humans KW - Hypnotics and Sedatives KW - Iatrogenic Disease KW - Infant KW - Infant, Newborn KW - Intensive Care Units, Pediatric KW - Italy KW - Logistic Models KW - Male KW - Prospective Studies KW - Respiration, Artificial KW - Substance Withdrawal Syndrome AB -

OBJECTIVES: Withdrawal syndrome is an adverse reaction of analgesic and sedative therapy, with a reported occurrence rate between 17% and 57% in critically ill children. Although some factors related to the development of withdrawal syndrome have been identified, there is weak evidence for the effectiveness of preventive and therapeutic strategies. The main aim of this study was to evaluate the frequency of withdrawal syndrome in Italian PICUs, using a validated instrument. We also analyzed differences in patient characteristics, analgesic and sedative treatment, and patients' outcome between patients with and without withdrawal syndrome.

DESIGN: Observational multicenter prospective study.

SETTING: Eight Italian PICUs belonging to the national PICU network Italian PICU network.

PATIENTS: One hundred thirteen patients, less than 18 years old, mechanically ventilated and treated with analgesic and sedative therapy for five or more days. They were admitted in PICU from November 2012 to May 2014.

INTERVENTIONS: Symptoms of withdrawal syndrome were monitored with Withdrawal Assessment Tool-1 scale.

MEASUREMENTS AND MAIN RESULTS: The occurrence rate of withdrawal syndrome was 64.6%. The following variables were significantly different between the patients who developed withdrawal syndrome and those who did not: type, duration, and cumulative dose of analgesic therapy; duration and cumulative dose of sedative therapy; clinical team judgment about analgesia and sedation's difficulty; and duration of analgesic weaning, mechanical ventilation, and PICU stay. Multivariate logistic regression analysis revealed that patients receiving morphine as their primary analgesic were 83% less likely to develop withdrawal syndrome than those receiving fentanyl or remifentanil.

CONCLUSIONS: Withdrawal syndrome was frequent in PICU patients, and patients with withdrawal syndrome had prolonged hospital treatment. We suggest adopting the lowest effective dose of analgesic and sedative drugs and frequent reevaluation of the need for continued use. Further studies are necessary to define common preventive and therapeutic strategies.

VL - 18 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28157809?dopt=Abstract ER - TY - JOUR T1 - Consensus Conference on Clinical Management of pediatric Atopic Dermatitis. JF - Ital J Pediatr Y1 - 2016 A1 - Galli, Elena A1 - Neri, Iria A1 - Ricci, Giampaolo A1 - Baldo, Ermanno A1 - Barone, Maurizio A1 - Belloni Fortina, Anna A1 - Bernardini, Roberto A1 - Berti, Irene A1 - Caffarelli, Carlo A1 - Calamelli, Elisabetta A1 - Capra, Lucetta A1 - Carello, Rossella A1 - Cipriani, Francesca A1 - Comberiati, Pasquale A1 - Diociaiuti, Andrea A1 - El Hachem, Maya A1 - Fontana, Elena A1 - Gruber, Michaela A1 - Haddock, Ellen A1 - Maiello, Nunzia A1 - Meglio, Paolo A1 - Patrizi, Annalisa A1 - Peroni, Diego A1 - Scarponi, Dorella A1 - Wielander, Ingrid A1 - Eichenfield, Lawrence F AB -

The Italian Consensus Conference on clinical management of atopic dermatitis in children reflects the best and most recent scientific evidence, with the aim to provide specialists with a useful tool for managing this common, but complex clinical condition. Thanks to the contribution of experts in the field and members of the Italian Society of Pediatric Allergology and Immunology (SIAIP) and the Italian Society of Pediatric Dermatology (SIDerP), this Consensus statement integrates the basic principles of the most recent guidelines for the management of atopic dermatitis to facilitate a practical approach to the disease. The therapeutical approach should be adapted to the clinical severity and requires a tailored strategy to ensure good compliance by children and their parents. In this Consensus, levels and models of intervention are also enriched by the Italian experience to facilitate a practical approach to the disease.

VL - 42 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26936273?dopt=Abstract ER - TY - JOUR T1 - Efficacy of ketamine in refractory convulsive status epilepticus in children: a protocol for a sequential design, multicentre, randomised, controlled, open-label, non-profit trial (KETASER01). JF - BMJ Open Y1 - 2016 A1 - Rosati, Anna A1 - Ilvento, Lucrezia A1 - L'Erario, Manuela A1 - De Masi, Salvatore A1 - Biggeri, Annibale A1 - Fabbro, Giancarlo A1 - Bianchi, Roberto A1 - Stoppa, Francesca A1 - Fusco, Lucia A1 - Pulitanò, Silvia A1 - Battaglia, Domenica A1 - Pettenazzo, Andrea A1 - Sartori, Stefano A1 - Biban, Paolo A1 - Fontana, Elena A1 - Cesaroni, Elisabetta A1 - Mora, Donatella A1 - Costa, Paola A1 - Meleleo, Rosanna A1 - Vittorini, Roberta A1 - Conio, Alessandra A1 - Wolfler, Andrea A1 - Mastrangelo, Massimo A1 - Mondardini, Maria Cristina A1 - Franzoni, Emilio A1 - McGreevy, Kathleen S A1 - Di Simone, Lorena A1 - Pugi, Alessandra A1 - Mirabile, Lorenzo A1 - Vigevano, Federico A1 - Guerrini, Renzo AB -

INTRODUCTION: Status epilepticus (SE) is a life-threatening neurological emergency. SE lasting longer than 120 min and not responding to first-line and second-line antiepileptic drugs is defined as 'refractory' (RCSE) and requires intensive care unit treatment. There is currently neither evidence nor consensus to guide either the optimal choice of therapy or treatment goals for RCSE, which is generally treated with coma induction using conventional anaesthetics (high dose midazolam, thiopental and/or propofol). Increasing evidence indicates that ketamine (KE), a strong N-methyl-d-aspartate glutamate receptor antagonist, may be effective in treating RCSE. We hypothesised that intravenous KE is more efficacious and safer than conventional anaesthetics in treating RCSE.

METHODS AND ANALYSIS: A multicentre, randomised, controlled, open-label, non-profit, sequentially designed study will be conducted to assess the efficacy of KE compared with conventional anaesthetics in the treatment of RCSE in children. 10 Italian centres/hospitals are involved in enrolling 57 patients aged 1 month to 18 years with RCSE. Primary outcome is the resolution of SE up to 24 hours after withdrawal of therapy and is updated for each patient treated according to the sequential method.

ETHICS AND DISSEMINATION: The study received ethical approval from the Tuscan Paediatric Ethics Committee (12/2015). The results of this study will be published in peer-reviewed journals and presented at international conferences.

TRIAL REGISTRATION NUMBER: NCT02431663; Pre-results.

VL - 6 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27311915?dopt=Abstract ER - TY - JOUR T1 - EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. JF - Brain Y1 - 2016 A1 - Byrne, Susan A1 - Jansen, Lara A1 - U-King-Im, Jean-Marie A1 - Siddiqui, Ata A1 - Lidov, Hart G W A1 - Bodi, Istvan A1 - Smith, Luke A1 - Mein, Rachael A1 - Cullup, Thomas A1 - Dionisi-Vici, Carlo A1 - Al-Gazali, Lihadh A1 - Al-Owain, Mohammed A1 - Bruwer, Zandre A1 - Al Thihli, Khalid A1 - El-Garhy, Rana A1 - Flanigan, Kevin M A1 - Manickam, Kandamurugu A1 - Zmuda, Erik A1 - Banks, Wesley A1 - Gershoni-Baruch, Ruth A1 - Mandel, Hanna A1 - Dagan, Efrat A1 - Raas-Rothschild, Annick A1 - Barash, Hila A1 - Filloux, Francis A1 - Creel, Donnell A1 - Harris, Michael A1 - Hamosh, Ada A1 - Kölker, Stefan A1 - Ebrahimi-Fakhari, Darius A1 - Hoffmann, Georg F A1 - Manchester, David A1 - Boyer, Philip J A1 - Manzur, Adnan Y A1 - Lourenco, Charles Marques A1 - Pilz, Daniela T A1 - Kamath, Arveen A1 - Prabhakar, Prab A1 - Rao, Vamshi K A1 - Rogers, R Curtis A1 - Ryan, Monique M A1 - Brown, Natasha J A1 - McLean, Catriona A A1 - Said, Edith A1 - Schara, Ulrike A1 - Stein, Anja A1 - Sewry, Caroline A1 - Travan, Laura A1 - Wijburg, Frits A A1 - Zenker, Martin A1 - Mohammed, Shehla A1 - Fanto, Manolis A1 - Gautel, Mathias A1 - Jungbluth, Heinz KW - Agenesis of Corpus Callosum KW - Animals KW - Autophagy KW - Cataract KW - Child, Preschool KW - Cross-Sectional Studies KW - Drosophila melanogaster KW - Female KW - Hippocampus KW - Humans KW - Male KW - Mutation KW - Neurodevelopmental Disorders KW - Proteins KW - Retrospective Studies AB -

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.

VL - 139 IS - Pt 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26917586?dopt=Abstract ER - TY - JOUR T1 - Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index. JF - Mol Psychiatry Y1 - 2016 A1 - Hinney, A A1 - Kesselmeier, M A1 - Jall, S A1 - Volckmar, A-L A1 - Föcker, M A1 - Antel, J A1 - Heid, I M A1 - Winkler, T W A1 - Grant, S F A A1 - Guo, Y A1 - Bergen, A W A1 - Kaye, W A1 - Berrettini, W A1 - Hakonarson, H A1 - Herpertz-Dahlmann, B A1 - de Zwaan, M A1 - Herzog, W A1 - Ehrlich, S A1 - Zipfel, S A1 - Egberts, K M A1 - Adan, R A1 - Brandys, M A1 - van Elburg, A A1 - Boraska Perica, V A1 - Franklin, C S A1 - Tschöp, M H A1 - Zeggini, E A1 - Bulik, C M A1 - Collier, D A1 - Scherag, A A1 - Müller, T D A1 - Hebebrand, J AB -

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10(-5), Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; Poverall: 2.47 × 10(-06)/Pfemales: 3.45 × 10(-07)/Pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.Molecular Psychiatry advance online publication, 17 May 2016; doi:10.1038/mp.2016.71.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27184124?dopt=Abstract ER - TY - JOUR T1 - Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. JF - Nat Commun Y1 - 2016 A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Gorski, Mathias A1 - Chu, Audrey Y A1 - Li, Man A1 - Mijatovic, Vladan A1 - Garnaas, Maija A1 - Tin, Adrienne A1 - Sorice, Rossella A1 - Li, Yong A1 - Taliun, Daniel A1 - Olden, Matthias A1 - Foster, Meredith A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Pers, Tune H A1 - Johnson, Andrew D A1 - Ko, Yi-An A1 - Fuchsberger, Christian A1 - Tayo, Bamidele A1 - Nalls, Michael A1 - Feitosa, Mary F A1 - Isaacs, Aaron A1 - Dehghan, Abbas A1 - d'Adamo, Pio A1 - Adeyemo, Adebowale A1 - Dieffenbach, Aida Karina A1 - Zonderman, Alan B A1 - Nolte, Ilja M A1 - van der Most, Peter J A1 - Wright, Alan F A1 - Shuldiner, Alan R A1 - Morrison, Alanna C A1 - Hofman, Albert A1 - Smith, Albert V A1 - Dreisbach, Albert W A1 - Franke, Andre A1 - Uitterlinden, André G A1 - Metspalu, Andres A1 - Tönjes, Anke A1 - Lupo, Antonio A1 - Robino, Antonietta A1 - Johansson, Åsa A1 - Demirkan, Ayse A1 - Kollerits, Barbara A1 - Freedman, Barry I A1 - Ponte, Belen A1 - Oostra, Ben A A1 - Paulweber, Bernhard A1 - Krämer, Bernhard K A1 - Mitchell, Braxton D A1 - Buckley, Brendan M A1 - Peralta, Carmen A A1 - Hayward, Caroline A1 - Helmer, Catherine A1 - Rotimi, Charles N A1 - Shaffer, Christian M A1 - Müller, Christian A1 - Sala, Cinzia A1 - van Duijn, Cornelia M A1 - Saint-Pierre, Aude A1 - Ackermann, Daniel A1 - Shriner, Daniel A1 - Ruggiero, Daniela A1 - Toniolo, Daniela A1 - Lu, Yingchang A1 - Cusi, Daniele A1 - Czamara, Darina A1 - Ellinghaus, David A1 - Siscovick, David S A1 - Ruderfer, Douglas A1 - Gieger, Christian A1 - Grallert, Harald A1 - Rochtchina, Elena A1 - Atkinson, Elizabeth J A1 - Holliday, Elizabeth G A1 - Boerwinkle, Eric A1 - Salvi, Erika A1 - Bottinger, Erwin P A1 - Murgia, Federico A1 - Rivadeneira, Fernando A1 - Ernst, Florian A1 - Kronenberg, Florian A1 - Hu, Frank B A1 - Navis, Gerjan J A1 - Curhan, Gary C A1 - Ehret, George B A1 - Homuth, Georg A1 - Coassin, Stefan A1 - Thun, Gian-Andri A1 - Pistis, Giorgio A1 - Gambaro, Giovanni A1 - Malerba, Giovanni A1 - Montgomery, Grant W A1 - Eiriksdottir, Gudny A1 - Jacobs, Gunnar A1 - Li, Guo A1 - Wichmann, H-Erich A1 - Campbell, Harry A1 - Schmidt, Helena A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Brenner, Hermann A1 - Kroemer, Heyo K A1 - Kramer, Holly A1 - Lin, Honghuang A1 - Leach, I Mateo A1 - Ford, Ian A1 - Guessous, Idris A1 - Rudan, Igor A1 - Prokopenko, Inga A1 - Borecki, Ingrid A1 - Heid, Iris M A1 - Kolcic, Ivana A1 - Persico, Ivana A1 - Jukema, J Wouter A1 - Wilson, James F A1 - Felix, Janine F A1 - Divers, Jasmin A1 - Lambert, Jean-Charles A1 - Stafford, Jeanette M A1 - Gaspoz, Jean-Michel A1 - Smith, Jennifer A A1 - Faul, Jessica D A1 - Wang, Jie Jin A1 - Ding, Jingzhong A1 - Hirschhorn, Joel N A1 - Attia, John A1 - Whitfield, John B A1 - Chalmers, John A1 - Viikari, Jorma A1 - Coresh, Josef A1 - Denny, Joshua C A1 - Karjalainen, Juha A1 - Fernandes, Jyotika K A1 - Endlich, Karlhans A1 - Butterbach, Katja A1 - Keene, Keith L A1 - Lohman, Kurt A1 - Portas, Laura A1 - Launer, Lenore J A1 - Lyytikäinen, Leo-Pekka A1 - Yengo, Loic A1 - Franke, Lude A1 - Ferrucci, Luigi A1 - Rose, Lynda M A1 - Kedenko, Lyudmyla A1 - Rao, Madhumathi A1 - Struchalin, Maksim A1 - Kleber, Marcus E A1 - Cavalieri, Margherita A1 - Haun, Margot A1 - Cornelis, Marilyn C A1 - Ciullo, Marina A1 - Pirastu, Mario A1 - de Andrade, Mariza A1 - McEvoy, Mark A A1 - Woodward, Mark A1 - Adam, Martin A1 - Cocca, Massimiliano A1 - Nauck, Matthias A1 - Imboden, Medea A1 - Waldenberger, Melanie A1 - Pruijm, Menno A1 - Metzger, Marie A1 - Stumvoll, Michael A1 - Evans, Michele K A1 - Sale, Michele M A1 - Kähönen, Mika A1 - Boban, Mladen A1 - Bochud, Murielle A1 - Rheinberger, Myriam A1 - Verweij, Niek A1 - Bouatia-Naji, Nabila A1 - Martin, Nicholas G A1 - Hastie, Nick A1 - Probst-Hensch, Nicole A1 - Soranzo, Nicole A1 - Devuyst, Olivier A1 - Raitakari, Olli A1 - Gottesman, Omri A1 - Franco, Oscar H A1 - Polasek, Ozren A1 - Gasparini, Paolo A1 - Munroe, Patricia B A1 - Ridker, Paul M A1 - Mitchell, Paul A1 - Muntner, Paul A1 - Meisinger, Christa A1 - Smit, Johannes H A1 - Kovacs, Peter A1 - Wild, Philipp S A1 - Froguel, Philippe A1 - Rettig, Rainer A1 - Mägi, Reedik A1 - Biffar, Reiner A1 - Schmidt, Reinhold A1 - Middelberg, Rita P S A1 - Carroll, Robert J A1 - Penninx, Brenda W A1 - Scott, Rodney J A1 - Katz, Ronit A1 - Sedaghat, Sanaz A1 - Wild, Sarah H A1 - Kardia, Sharon L R A1 - Ulivi, Sheila A1 - Hwang, Shih-Jen A1 - Enroth, Stefan A1 - Kloiber, Stefan A1 - Trompet, Stella A1 - Stengel, Bénédicte A1 - Hancock, Stephen J A1 - Turner, Stephen T A1 - Rosas, Sylvia E A1 - Stracke, Sylvia A1 - Harris, Tamara B A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Lehtimäki, Terho A1 - Illig, Thomas A1 - Aspelund, Thor A1 - Nikopensius, Tiit A1 - Esko, Tõnu A1 - Tanaka, Toshiko A1 - Gyllensten, Ulf A1 - Völker, Uwe A1 - Emilsson, Valur A1 - Vitart, Veronique A1 - Aalto, Ville A1 - Gudnason, Vilmundur A1 - Chouraki, Vincent A1 - Chen, Wei-Min A1 - Igl, Wilmar A1 - März, Winfried A1 - Koenig, Wolfgang A1 - Lieb, Wolfgang A1 - Loos, Ruth J F A1 - Liu, Yongmei A1 - Snieder, Harold A1 - Pramstaller, Peter P A1 - Parsa, Afshin A1 - O'Connell, Jeffrey R A1 - Susztak, Katalin A1 - Hamet, Pavel A1 - Tremblay, Johanne A1 - de Boer, Ian H A1 - Böger, Carsten A A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Köttgen, Anna A1 - Kao, W H Linda A1 - Fox, Caroline S KW - Gene Expression Regulation KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Renal Insufficiency, Chronic AB -

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

VL - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26831199?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies 74 loci associated with educational attainment. JF - Nature Y1 - 2016 A1 - Okbay, Aysu A1 - Beauchamp, Jonathan P A1 - Fontana, Mark Alan A1 - Lee, James J A1 - Pers, Tune H A1 - Rietveld, Cornelius A A1 - Turley, Patrick A1 - Chen, Guo-Bo A1 - Emilsson, Valur A1 - Meddens, S Fleur W A1 - Oskarsson, Sven A1 - Pickrell, Joseph K A1 - Thom, Kevin A1 - Timshel, Pascal A1 - de Vlaming, Ronald A1 - Abdellaoui, Abdel A1 - Ahluwalia, Tarunveer S A1 - Bacelis, Jonas A1 - Baumbach, Clemens A1 - Bjornsdottir, Gyda A1 - Brandsma, Johannes H A1 - Pina Concas, Maria A1 - Derringer, Jaime A1 - Furlotte, Nicholas A A1 - Galesloot, Tessel E A1 - Girotto, Giorgia A1 - Gupta, Richa A1 - Hall, Leanne M A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Horikoshi, Momoko A1 - Huffman, Jennifer E A1 - Kaasik, Kadri A1 - Kalafati, Ioanna P A1 - Karlsson, Robert A1 - Kong, Augustine A1 - Lahti, Jari A1 - van der Lee, Sven J A1 - deLeeuw, Christiaan A1 - Lind, Penelope A A1 - Lindgren, Karl-Oskar A1 - Liu, Tian A1 - Mangino, Massimo A1 - Marten, Jonathan A1 - Mihailov, Evelin A1 - Miller, Michael B A1 - van der Most, Peter J A1 - Oldmeadow, Christopher A1 - Payton, Antony A1 - Pervjakova, Natalia A1 - Peyrot, Wouter J A1 - Qian, Yong A1 - Raitakari, Olli A1 - Rueedi, Rico A1 - Salvi, Erika A1 - Schmidt, Börge A1 - Schraut, Katharina E A1 - Shi, Jianxin A1 - Smith, Albert V A1 - Poot, Raymond A A1 - St Pourcain, Beate A1 - Teumer, Alexander A1 - Thorleifsson, Gudmar A1 - Verweij, Niek A1 - Vuckovic, Dragana A1 - Wellmann, Juergen A1 - Westra, Harm-Jan A1 - Yang, Jingyun A1 - Zhao, Wei A1 - Zhu, Zhihong A1 - Alizadeh, Behrooz Z A1 - Amin, Najaf A1 - Bakshi, Andrew A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bønnelykke, Klaus A1 - Boyle, Patricia A A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Davies, Gail A1 - De Neve, Jan-Emmanuel A1 - Deloukas, Panos A1 - Demuth, Ilja A1 - Ding, Jun A1 - Eibich, Peter A1 - Eisele, Lewin A1 - Eklund, Niina A1 - Evans, David M A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Forstner, Andreas J A1 - Gandin, Ilaria A1 - Gunnarsson, Bjarni A1 - Halldórsson, Bjarni V A1 - Harris, Tamara B A1 - Heath, Andrew C A1 - Hocking, Lynne J A1 - Holliday, Elizabeth G A1 - Homuth, Georg A1 - Horan, Michael A A1 - Hottenga, Jouke-Jan A1 - de Jager, Philip L A1 - Joshi, Peter K A1 - Jugessur, Astanand A1 - Kaakinen, Marika A A1 - Kähönen, Mika A1 - Kanoni, Stavroula A1 - Keltigangas-Järvinen, Liisa A1 - Kiemeney, Lambertus A L M A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kraja, Aldi T A1 - Kroh, Martin A1 - Kutalik, Zoltán A1 - Latvala, Antti A1 - Launer, Lenore J A1 - Lebreton, Maël P A1 - Levinson, Douglas F A1 - Lichtenstein, Paul A1 - Lichtner, Peter A1 - Liewald, David C M A1 - Loukola, Anu A1 - Madden, Pamela A A1 - Mägi, Reedik A1 - Mäki-Opas, Tomi A1 - Marioni, Riccardo E A1 - Marques-Vidal, Pedro A1 - Meddens, Gerardus A A1 - McMahon, George A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Milaneschi, Yusplitri A1 - Milani, Lili A1 - Montgomery, Grant W A1 - Myhre, Ronny A1 - Nelson, Christopher P A1 - Nyholt, Dale R A1 - Ollier, William E R A1 - Palotie, Aarno A1 - Paternoster, Lavinia A1 - Pedersen, Nancy L A1 - Petrovic, Katja E A1 - Porteous, David J A1 - Räikkönen, Katri A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rostapshova, Olga A1 - Rudan, Igor A1 - Rustichini, Aldo A1 - Salomaa, Veikko A1 - Sanders, Alan R A1 - Sarin, Antti-Pekka A1 - Schmidt, Helena A1 - Scott, Rodney J A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Staessen, Jan A A1 - Steinhagen-Thiessen, Elisabeth A1 - Strauch, Konstantin A1 - Terracciano, Antonio A1 - Tobin, Martin D A1 - Ulivi, Sheila A1 - Vaccargiu, Simona A1 - Quaye, Lydia A1 - van Rooij, Frank J A A1 - Venturini, Cristina A1 - Vinkhuyzen, Anna A E A1 - Völker, Uwe A1 - Völzke, Henry A1 - Vonk, Judith M A1 - Vozzi, Diego A1 - Waage, Johannes A1 - Ware, Erin B A1 - Willemsen, Gonneke A1 - Attia, John R A1 - Bennett, David A A1 - Berger, Klaus A1 - Bertram, Lars A1 - Bisgaard, Hans A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bültmann, Ute A1 - Chabris, Christopher F A1 - Cucca, Francesco A1 - Cusi, Daniele A1 - Deary, Ian J A1 - Dedoussis, George V A1 - van Duijn, Cornelia M A1 - Eriksson, Johan G A1 - Franke, Barbara A1 - Franke, Lude A1 - Gasparini, Paolo A1 - Gejman, Pablo V A1 - Gieger, Christian A1 - Grabe, Hans-Jörgen A1 - Gratten, Jacob A1 - Groenen, Patrick J F A1 - Gudnason, Vilmundur A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - Hinds, David A A1 - Hoffmann, Wolfgang A1 - Hyppönen, Elina A1 - Iacono, William G A1 - Jacobsson, Bo A1 - Järvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Kaprio, Jaakko A1 - Kardia, Sharon L R A1 - Lehtimäki, Terho A1 - Lehrer, Steven F A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - McGue, Matt A1 - Metspalu, Andres A1 - Pendleton, Neil A1 - Penninx, Brenda W J H A1 - Perola, Markus A1 - Pirastu, Nicola A1 - Pirastu, Mario A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Power, Christine A1 - Province, Michael A A1 - Samani, Nilesh J A1 - Schlessinger, David A1 - Schmidt, Reinhold A1 - Sørensen, Thorkild I A A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Thorsteinsdottir, Unnur A1 - Thurik, A Roy A1 - Timpson, Nicholas J A1 - Tiemeier, Henning A1 - Tung, Joyce Y A1 - Uitterlinden, André G A1 - Vitart, Veronique A1 - Vollenweider, Peter A1 - Weir, David R A1 - Wilson, James F A1 - Wright, Alan F A1 - Conley, Dalton C A1 - Krueger, Robert F A1 - Davey Smith, George A1 - Hofman, Albert A1 - Laibson, David I A1 - Medland, Sarah E A1 - Meyer, Michelle N A1 - Yang, Jian A1 - Johannesson, Magnus A1 - Visscher, Peter M A1 - Esko, Tõnu A1 - Koellinger, Philipp D A1 - Cesarini, David A1 - Benjamin, Daniel J KW - Alzheimer Disease KW - Bipolar Disorder KW - Brain KW - Cognition KW - Computational Biology KW - Educational Status KW - Fetus KW - Gene Expression Regulation KW - Gene-Environment Interaction KW - Genome-Wide Association Study KW - Great Britain KW - Humans KW - Molecular Sequence Annotation KW - Polymorphism, Single Nucleotide KW - Schizophrenia AB -

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

VL - 533 IS - 7604 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27225129?dopt=Abstract ER - TY - JOUR T1 - A Genome-Wide Association Study in isolated populations reveals new genes associated to common food likings. JF - Rev Endocr Metab Disord Y1 - 2016 A1 - Pirastu, Nicola A1 - Kooyman, Maarten A1 - Traglia, Michela A1 - Robino, Antonietta A1 - Willems, Sara M A1 - Pistis, Giorgio A1 - Amin, Najaf A1 - Sala, Cinzia A1 - Karssen, Lennart C A1 - van Duijn, Cornelia A1 - Toniolo, Daniela A1 - Gasparini, Paolo AB -

Food preferences are the first factor driving food choice and thus nutrition. They involve numerous different senses such as taste and olfaction as well as various other factors such as personal experiences and hedonistic aspects. Although it is clear that several of these have a genetic basis, up to now studies have focused mostly on the effects of polymorphisms of taste receptor genes. Therefore, we have carried out one of the first large scale (4611 individuals) GWAS on food likings assessed for 20 specific food likings belonging to 4 different categories (vegetables, fatty, dairy and bitter). A two-step meta-analysis using three different isolated populations from Italy for the discovery step and two populations from The Netherlands and Central Asia for replication, revealed 15 independent genome-wide significant loci (p < 5 × 10(-8)) for 12 different foods. None of the identified genes coded for either taste or olfactory receptors suggesting that genetics impacts in determining food likings in a much broader way than simple differences in taste perception. These results represent a further step in uncovering the genes that underlie liking of common foods that in the end will greatly help understanding the genetics of human nutrition in general.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27129595?dopt=Abstract ER - TY - JOUR T1 - Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal. JF - Sci Rep Y1 - 2016 A1 - Risso, Davide S A1 - Mezzavilla, Massimo A1 - Pagani, Luca A1 - Robino, Antonietta A1 - Morini, Gabriella A1 - Tofanelli, Sergio A1 - Carrai, Maura A1 - Campa, Daniele A1 - Barale, Roberto A1 - Caradonna, Fabio A1 - Gasparini, Paolo A1 - Luiselli, Donata A1 - Wooding, Stephen A1 - Drayna, Dennis AB -

The ability to taste phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) is a polymorphic trait mediated by the TAS2R38 bitter taste receptor gene. It has long been hypothesized that global genetic diversity at this locus evolved under pervasive pressures from balancing natural selection. However, recent high-resolution population genetic studies of TAS2Rs suggest that demographic events have played a critical role in the evolution of these genes. We here utilized the largest TAS2R38 database yet analyzed, consisting of 5,589 individuals from 105 populations, to examine natural selection, haplotype frequencies and linkage disequilibrium to estimate the effects of both selection and demography on contemporary patterns of variation at this locus. We found signs of an ancient balancing selection acting on this gene but no post Out-Of-Africa departures from neutrality, implying that the current observed patterns of variation can be predominantly explained by demographic, rather than selective events. In addition, we found signatures of ancient selective forces acting on different African TAS2R38 haplotypes. Collectively our results provide evidence for a relaxation of recent selective forces acting on this gene and a revised hypothesis for the origins of the present-day worldwide distribution of TAS2R38 haplotypes.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27138342?dopt=Abstract ER - TY - JOUR T1 - The Importance of Mortality Risk Assessment: Validation of the Pediatric Index of Mortality 3 Score. JF - Pediatr Crit Care Med Y1 - 2016 A1 - Wolfler, Andrea A1 - Osello, Raffaella A1 - Gualino, Jenny A1 - Calderini, Edoardo A1 - Vigna, Gianluca A1 - Santuz, Pierantonio A1 - Amigoni, Angela A1 - Savron, Fabio A1 - Caramelli, Fabio A1 - Rossetti, Emanuele A1 - Cecchetti, Corrado A1 - Corbari, Maurizio A1 - Piastra, Marco A1 - Testa, Raffaele A1 - Coffaro, Giancarlo A1 - Stancanelli, Giusi A1 - Gitto, Eloisa A1 - Amato, Roberta A1 - Prinelli, Federica A1 - Salvo, Ida AB -

OBJECTIVE: To evaluate the performance of the newest version of the Pediatric Index of Mortality 3 score and compare it with the Pediatric Index of Mortality 2 in a multicenter national cohort of children admitted to PICU.

DESIGN: Retrospective, prospective cohort study.

SETTING: Seventeen Italian PICUs.

PATIENTS: All children 0 to 15 years old admitted in PICU from January 2010 to October 2014.

INTERVENTIONS: None.

MEASUREMENT AND MAIN RESULTS: Eleven thousand one hundred nine children were enrolled in the study. The mean Pediatric Index of Mortality 2 and 3 values of 4.9 and 3.9, respectively, differed significantly (p < 0.05). Overall mortality rate was 3.9%, and the standardized mortality ratio was 0.80 for Pediatric Index of Mortality 2 and 0.98 for Pediatric Index of Mortality 3 (p < 0.05). The area under the curve of the receiver operating characteristic curves was similar for Pediatric Index of Mortality 2 and Pediatric Index of Mortality 3. The Hosmer-Lemeshow test was not significant for Pediatric Index of Mortality 3 (p = 0.21) but was highly significant for Pediatric Index of Mortality 2 (p < 0.001), which overestimated death mainly in high-risk categories.

CONCLUSIONS: Mortality indices require validation in each country where it is used. The new Pediatric Index of Mortality 3 score performed well in an Italian population. Both calibration and discrimination were appropriate, and the score more accurately predicted the mortality risk than Pediatric Index of Mortality 2.

VL - 17 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26825046?dopt=Abstract ER - TY - JOUR T1 - Plant Elite Squad: First Defense Line and Resistance Genes - Identification, Diversity and Functional Roles. JF - Curr Protein Pept Sci Y1 - 2016 A1 - Wanderley-Nogueira, Ana Carolina A1 - Bezerra-Neto, João Pacífico A1 - Kido, Éderson Akio A1 - de Araújo, Flávia Tadeu A1 - Amorim, Lidiane Lindinalva Barbosa A1 - Crovella, Sergio A1 - Benko-Iseppon, Ana Maria AB -

Plants exhibit sensitive mechanisms to respond to environmental stresses, presenting some specific and non-specific reactions when attacked by pathogens, including organisms from different classes and complexity, as viroids, viruses, bacteria, fungi and nematodes. A crucial step to define the fate of the plant facing an invading pathogen is the activation of a compatible Resistance (R) gene, the focus of the present review. Different aspects regarding R-genes and their products are discussed, including pathogen recognition mechanisms, signaling and effects on induced and constitutive defense processes, splicing and post transcriptional mechanisms involved. There are still countless challenges to the complete understanding of the mechanisms involving R-genes in plants, in particular those related to the interactions with other genes of the pathogen and of the host itself, their regulation, acting mechanisms at transcriptional and post-transcriptional levels, as well as the influence of other types of stress over their regulation. A magnification of knowledge is expected when considering the novel information from the omics and systems biology.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27455974?dopt=Abstract ER - TY - JOUR T1 - A reference panel of 64,976 haplotypes for genotype imputation. JF - Nat Genet Y1 - 2016 A1 - McCarthy, Shane A1 - Das, Sayantan A1 - Kretzschmar, Warren A1 - Delaneau, Olivier A1 - Wood, Andrew R A1 - Teumer, Alexander A1 - Kang, Hyun Min A1 - Fuchsberger, Christian A1 - Danecek, Petr A1 - Sharp, Kevin A1 - Luo, Yang A1 - Sidore, Carlo A1 - Kwong, Alan A1 - Timpson, Nicholas A1 - Koskinen, Seppo A1 - Vrieze, Scott A1 - Scott, Laura J A1 - Zhang, He A1 - Mahajan, Anubha A1 - Veldink, Jan A1 - Peters, Ulrike A1 - Pato, Carlos A1 - van Duijn, Cornelia M A1 - Gillies, Christopher E A1 - Gandin, Ilaria A1 - Mezzavilla, Massimo A1 - Gilly, Arthur A1 - Cocca, Massimiliano A1 - Traglia, Michela A1 - Angius, Andrea A1 - Barrett, Jeffrey C A1 - Boomsma, Dorrett A1 - Branham, Kari A1 - Breen, Gerome A1 - Brummett, Chad M A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Chan, Andrew A1 - Chen, Sai A1 - Chew, Emily A1 - Collins, Francis S A1 - Corbin, Laura J A1 - Smith, George Davey A1 - Dedoussis, George A1 - Dörr, Marcus A1 - Farmaki, Aliki-Eleni A1 - Ferrucci, Luigi A1 - Forer, Lukas A1 - Fraser, Ross M A1 - Gabriel, Stacey A1 - Levy, Shawn A1 - Groop, Leif A1 - Harrison, Tabitha A1 - Hattersley, Andrew A1 - Holmen, Oddgeir L A1 - Hveem, Kristian A1 - Kretzler, Matthias A1 - Lee, James C A1 - McGue, Matt A1 - Meitinger, Thomas A1 - Melzer, David A1 - Min, Josine L A1 - Mohlke, Karen L A1 - Vincent, John B A1 - Nauck, Matthias A1 - Nickerson, Deborah A1 - Palotie, Aarno A1 - Pato, Michele A1 - Pirastu, Nicola A1 - McInnis, Melvin A1 - Richards, J Brent A1 - Sala, Cinzia A1 - Salomaa, Veikko A1 - Schlessinger, David A1 - Schoenherr, Sebastian A1 - Slagboom, P Eline A1 - Small, Kerrin A1 - Spector, Timothy A1 - Stambolian, Dwight A1 - Tuke, Marcus A1 - Tuomilehto, Jaakko A1 - Van den Berg, Leonard H A1 - van Rheenen, Wouter A1 - Völker, Uwe A1 - Wijmenga, Cisca A1 - Toniolo, Daniela A1 - Zeggini, Eleftheria A1 - Gasparini, Paolo A1 - Sampson, Matthew G A1 - Wilson, James F A1 - Frayling, Timothy A1 - de Bakker, Paul I W A1 - Swertz, Morris A A1 - McCarroll, Steven A1 - Kooperberg, Charles A1 - Dekker, Annelot A1 - Altshuler, David A1 - Willer, Cristen A1 - Iacono, William A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Walter, Klaudia A1 - Swaroop, Anand A1 - Cucca, Francesco A1 - Anderson, Carl A A1 - Myers, Richard M A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Durbin, Richard AB -

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27548312?dopt=Abstract ER - TY - JOUR T1 - Resistance (R) Genes: Applications and Prospects for Plant Biotechnology and Breeding. JF - Curr Protein Pept Sci Y1 - 2016 A1 - Pandolfi, Valesca A1 - Neto, José Ribamar Costa Ferreira A1 - Silva, Manassés Daniel A1 - Amorim, Lidiane Lindinalva Barbosa A1 - Wanderley-Nogueira, Ana Carolina A1 - de Oliveira Silva, Roberta Lane A1 - Kido, Éderson Akio A1 - Crovella, Sergio A1 - Iseppon, Ana Maria Benko AB -

The discovery of novel plant resistance (R) genes (including their homologs and analogs) opened interesting possibilities for controlling plant diseases caused by several pathogens. However, due to environmental pressure and high selection operated by pathogens, several crop plants have lost specificity, broad-spectrum or durability of resistance. On the other hand, the advances in plant genome sequencing and biotechnological approaches, combined with the increasing knowledge on R-genes have provided new insights on their applications for plant genetic breeding, allowing the identification and implementation of novel and efficient strategies that enhance or optimize their use for efficiently controlling plant diseases. The present review focuses on main perspectives of application of R-genes and its co-players for the acquisition of resistance to pathogens in cultivated plants, with emphasis on biotechnological inferences, including transgenesis, cisgenesis, directed mutagenesis and gene editing, with examples of success and challenges to be faced.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/27455971?dopt=Abstract ER - TY - JOUR T1 - Analgesia by cooling vibration during venipuncture in children with cognitive impairment. JF - Acta Paediatr Y1 - 2015 A1 - Schreiber, Silvana A1 - Cozzi, Giorgio A1 - Rutigliano, Rosaria A1 - Assandro, Paola A1 - Tubaro, Martina A1 - Cortellazzo Wiel, Luisa A1 - Ronfani, Luca A1 - Barbi, Egidio AB -

AIM: Children with cognitive impairment experience pain more frequently than healthy children and are more likely to require venipuncture or intravenous cannulation for various procedures. They are frequently unable to report pain and often receive poor pain assessment and management. This study assessed the effectiveness of physical analgesia during vascular access in children with cognitive impairments.

METHODS: We conducted a prospective randomised controlled study at a tertiary-level children's hospital in Italy from April to May 2015 to assess whether a cooling vibration device called Buzzy decreased pain during venipuncture and intravenous cannulation in children with cognitive impairment. None of the children had verbal skills and the main cognitive impairments were cerebral palsy, epileptic encephalopathy and genetic syndromes.

RESULTS: We tested 70 children with a median age of nine years: 34 in the Buzzy group and 36 in the no-intervention group. Parents were trained in the use of the Noncommunicating Children's Pain Checklist - postoperative version scale, and they reported no or mild procedural pain in 32 cases (91.4%) in the Buzzy group and in 22 cases (61.1%) in the no-intervention group (p = 0.003).

CONCLUSION: Cooling vibration analgesia during vascular access reduced pain in children with cognitive impairment.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/26401633?dopt=Abstract ER - TY - JOUR T1 - Directional dominance on stature and cognition in diverse human populations. JF - Nature Y1 - 2015 A1 - Joshi, Peter K A1 - Esko, Tõnu A1 - Mattsson, Hannele A1 - Eklund, Niina A1 - Gandin, Ilaria A1 - Nutile, Teresa A1 - Jackson, Anne U A1 - Schurmann, Claudia A1 - Smith, Albert V A1 - Zhang, Weihua A1 - Okada, Yukinori A1 - Stančáková, Alena A1 - Faul, Jessica D A1 - Zhao, Wei A1 - Bartz, Traci M A1 - Concas, Maria Pina A1 - Franceschini, Nora A1 - Enroth, Stefan A1 - Vitart, Veronique A1 - Trompet, Stella A1 - Guo, Xiuqing A1 - Chasman, Daniel I A1 - O'Connel, Jeffrey R A1 - Corre, Tanguy A1 - Nongmaithem, Suraj S A1 - Chen, Yuning A1 - Mangino, Massimo A1 - Ruggiero, Daniela A1 - Traglia, Michela A1 - Farmaki, Aliki-Eleni A1 - Kacprowski, Tim A1 - Bjonnes, Andrew A1 - van der Spek, Ashley A1 - Wu, Ying A1 - Giri, Anil K A1 - Yanek, Lisa R A1 - Wang, Lihua A1 - Hofer, Edith A1 - Rietveld, Cornelius A A1 - McLeod, Olga A1 - Cornelis, Marilyn C A1 - Pattaro, Cristian A1 - Verweij, Niek A1 - Baumbach, Clemens A1 - Abdellaoui, Abdel A1 - Warren, Helen R A1 - Vuckovic, Dragana A1 - Mei, Hao A1 - Bouchard, Claude A1 - Perry, John R B A1 - Cappellani, Stefania A1 - Mirza, Saira S A1 - Benton, Miles C A1 - Broeckel, Ulrich A1 - Medland, Sarah E A1 - Lind, Penelope A A1 - Malerba, Giovanni A1 - Drong, Alexander A1 - Yengo, Loic A1 - Bielak, Lawrence F A1 - Zhi, Degui A1 - van der Most, Peter J A1 - Shriner, Daniel A1 - Mägi, Reedik A1 - Hemani, Gibran A1 - Karaderi, Tugce A1 - Wang, Zhaoming A1 - Liu, Tian A1 - Demuth, Ilja A1 - Zhao, Jing Hua A1 - Meng, Weihua A1 - Lataniotis, Lazaros A1 - van der Laan, Sander W A1 - Bradfield, Jonathan P A1 - Wood, Andrew R A1 - Bonnefond, Amelie A1 - Ahluwalia, Tarunveer S A1 - Hall, Leanne M A1 - Salvi, Erika A1 - Yazar, Seyhan A1 - Carstensen, Lisbeth A1 - de Haan, Hugoline G A1 - Abney, Mark A1 - Afzal, Uzma A1 - Allison, Matthew A A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Barr, R Graham A1 - Baumeister, Sebastian E A1 - Benjamin, Daniel J A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Campbell, Archie A1 - Chakravarti, Aravinda A1 - Chan, Yingleong A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Chen, Y-D Ida A1 - Collins, Francis S A1 - Connell, John A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Smith, George Davey A1 - Davies, Gail A1 - Dörr, Marcus A1 - Ehret, Georg A1 - Ellis, Stephen B A1 - Feenstra, Bjarke A1 - Feitosa, Mary F A1 - Ford, Ian A1 - Fox, Caroline S A1 - Frayling, Timothy M A1 - Friedrich, Nele A1 - Geller, Frank A1 - Scotland, Generation A1 - Gillham-Nasenya, Irina A1 - Gottesman, Omri A1 - Graff, Misa A1 - Grodstein, Francine A1 - Gu, Charles A1 - Haley, Chris A1 - Hammond, Christopher J A1 - Harris, Sarah E A1 - Harris, Tamara B A1 - Hastie, Nicholas D A1 - Heard-Costa, Nancy L A1 - Heikkilä, Kauko A1 - Hocking, Lynne J A1 - Homuth, Georg A1 - Hottenga, Jouke-Jan A1 - Huang, Jinyan A1 - Huffman, Jennifer E A1 - Hysi, Pirro G A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Joensuu, Anni A1 - Johansson, Åsa A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanoni, Stavroula A1 - Kerr, Shona M A1 - Khan, Nazir M A1 - Koellinger, Philipp A1 - Koistinen, Heikki A A1 - Kooner, Manraj K A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lahti, Jari A1 - Launer, Lenore J A1 - Lea, Rodney A A1 - Lehne, Benjamin A1 - Lehtimäki, Terho A1 - Liewald, David C M A1 - Lind, Lars A1 - Loh, Marie A1 - Lokki, Marja-Liisa A1 - London, Stephanie J A1 - Loomis, Stephanie J A1 - Loukola, Anu A1 - Lu, Yingchang A1 - Lumley, Thomas A1 - Lundqvist, Annamari A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Masciullo, Corrado A1 - Matchan, Angela A1 - Mathias, Rasika A A1 - Matsuda, Koichi A1 - Meigs, James B A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Mentch, Frank D A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Montasser, May E A1 - Montgomery, Grant W A1 - Morrison, Alanna A1 - Myers, Richard H A1 - Nadukuru, Rajiv A1 - Navarro, Pau A1 - Nelis, Mari A1 - Nieminen, Markku S A1 - Nolte, Ilja M A1 - O'Connor, George T A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Pankow, James S A1 - Patarcic, Inga A1 - Pavani, Francesca A1 - Peyser, Patricia A A1 - Pietilainen, Kirsi A1 - Poulter, Neil A1 - Prokopenko, Inga A1 - Ralhan, Sarju A1 - Redmond, Paul A1 - Rich, Stephen S A1 - Rissanen, Harri A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rose, Richard A1 - Sala, Cinzia A1 - Salako, Babatunde A1 - Salomaa, Veikko A1 - Sarin, Antti-Pekka A1 - Saxena, Richa A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sennblad, Bengt A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Shrestha, Smeeta A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Soranzo, Nicole A1 - Sotoodehnia, Nona A1 - Southam, Lorraine A1 - Stanton, Alice V A1 - Stathopoulou, Maria G A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Suderman, Matthew J A1 - Tandon, Nikhil A1 - Tang, Sian-Tsun A1 - Taylor, Kent D A1 - Tayo, Bamidele O A1 - Töglhofer, Anna Maria A1 - Tomaszewski, Maciej A1 - Tšernikova, Natalia A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van Hylckama Vlieg, Astrid A1 - van Setten, Jessica A1 - Vasankari, Tuula A1 - Vedantam, Sailaja A1 - Vlachopoulou, Efthymia A1 - Vozzi, Diego A1 - Vuoksimaa, Eero A1 - Waldenberger, Melanie A1 - Ware, Erin B A1 - Wentworth-Shields, William A1 - Whitfield, John B A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Yajnik, Chittaranjan S A1 - Yao, Jie A1 - Zaza, Gianluigi A1 - Zhu, Xiaofeng A1 - Salem, Rany M A1 - Melbye, Mads A1 - Bisgaard, Hans A1 - Samani, Nilesh J A1 - Cusi, Daniele A1 - Mackey, David A A1 - Cooper, Richard S A1 - Froguel, Philippe A1 - Pasterkamp, Gerard A1 - Grant, Struan F A A1 - Hakonarson, Hakon A1 - Ferrucci, Luigi A1 - Scott, Robert A A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Bertram, Lars A1 - Lindenberger, Ulman A1 - Berndt, Sonja I A1 - Lindgren, Cecilia M A1 - Timpson, Nicholas J A1 - Tönjes, Anke A1 - Munroe, Patricia B A1 - Sørensen, Thorkild I A A1 - Rotimi, Charles N A1 - Arnett, Donna K A1 - Oldehinkel, Albertine J A1 - Kardia, Sharon L R A1 - Balkau, Beverley A1 - Gambaro, Giovanni A1 - Morris, Andrew P A1 - Eriksson, Johan G A1 - Wright, Margie J A1 - Martin, Nicholas G A1 - Hunt, Steven C A1 - Starr, John M A1 - Deary, Ian J A1 - Griffiths, Lyn R A1 - Tiemeier, Henning A1 - Pirastu, Nicola A1 - Kaprio, Jaakko A1 - Wareham, Nicholas J A1 - Pérusse, Louis A1 - Wilson, James G A1 - Girotto, Giorgia A1 - Caulfield, Mark J A1 - Raitakari, Olli A1 - Boomsma, Dorret I A1 - Gieger, Christian A1 - van der Harst, Pim A1 - Hicks, Andrew A A1 - Kraft, Peter A1 - Sinisalo, Juha A1 - Knekt, Paul A1 - Johannesson, Magnus A1 - Magnusson, Patrik K E A1 - Hamsten, Anders A1 - Schmidt, Reinhold A1 - Borecki, Ingrid B A1 - Vartiainen, Erkki A1 - Becker, Diane M A1 - Bharadwaj, Dwaipayan A1 - Mohlke, Karen L A1 - Boehnke, Michael A1 - van Duijn, Cornelia M A1 - Sanghera, Dharambir K A1 - Teumer, Alexander A1 - Zeggini, Eleftheria A1 - Metspalu, Andres A1 - Gasparini, Paolo A1 - Ulivi, Sheila A1 - Ober, Carole A1 - Toniolo, Daniela A1 - Rudan, Igor A1 - Porteous, David J A1 - Ciullo, Marina A1 - Spector, Tim D A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Loos, Ruth J F A1 - Wright, Alan F A1 - Chandak, Giriraj R A1 - Vollenweider, Peter A1 - Shuldiner, Alan R A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Sattar, Naveed A1 - Gyllensten, Ulf A1 - North, Kari E A1 - Pirastu, Mario A1 - Psaty, Bruce M A1 - Weir, David R A1 - Laakso, Markku A1 - Gudnason, Vilmundur A1 - Takahashi, Atsushi A1 - Chambers, John C A1 - Kooner, Jaspal S A1 - Strachan, David P A1 - Campbell, Harry A1 - Hirschhorn, Joel N A1 - Perola, Markus A1 - Polasek, Ozren A1 - Wilson, James F KW - Biological Evolution KW - Blood Pressure KW - Body Height KW - Cholesterol, LDL KW - Cognition KW - Cohort Studies KW - Educational Status KW - Female KW - Forced Expiratory Volume KW - Genome, Human KW - Homozygote KW - Humans KW - Lung Volume Measurements KW - Male KW - Phenotype AB -

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

VL - 523 IS - 7561 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract ER - TY - JOUR T1 - Genetic studies of body mass index yield new insights for obesity biology. JF - Nature Y1 - 2015 A1 - Locke, Adam E A1 - Kahali, Bratati A1 - Berndt, Sonja I A1 - Justice, Anne E A1 - Pers, Tune H A1 - Day, Felix R A1 - Powell, Corey A1 - Vedantam, Sailaja A1 - Buchkovich, Martin L A1 - Yang, Jian A1 - Croteau-Chonka, Damien C A1 - Esko, Tõnu A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gustafsson, Stefan A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Wood, Andrew R A1 - Workalemahu, Tsegaselassie A1 - Faul, Jessica D A1 - Smith, Jennifer A A1 - Hua Zhao, Jing A1 - Zhao, Wei A1 - Chen, Jin A1 - Fehrmann, Rudolf A1 - Hedman, Åsa K A1 - Karjalainen, Juha A1 - Schmidt, Ellen M A1 - Absher, Devin A1 - Amin, Najaf A1 - Anderson, Denise A1 - Beekman, Marian A1 - Bolton, Jennifer L A1 - Bragg-Gresham, Jennifer L A1 - Buyske, Steven A1 - Demirkan, Ayse A1 - Deng, Guohong A1 - Ehret, Georg B A1 - Feenstra, Bjarke A1 - Feitosa, Mary F A1 - Fischer, Krista A1 - Goel, Anuj A1 - Gong, Jian A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - Kristiansson, Kati A1 - Lim, Unhee A1 - Lotay, Vaneet A1 - Mangino, Massimo A1 - Mateo Leach, Irene A1 - Medina-Gomez, Carolina A1 - Medland, Sarah E A1 - Nalls, Michael A A1 - Palmer, Cameron D A1 - Pasko, Dorota A1 - Pechlivanis, Sonali A1 - Peters, Marjolein J A1 - Prokopenko, Inga A1 - Shungin, Dmitry A1 - Stančáková, Alena A1 - Strawbridge, Rona J A1 - Ju Sung, Yun A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Trompet, Stella A1 - van der Laan, Sander W A1 - van Setten, Jessica A1 - Van Vliet-Ostaptchouk, Jana V A1 - Wang, Zhaoming A1 - Yengo, Loic A1 - Zhang, Weihua A1 - Isaacs, Aaron A1 - Albrecht, Eva A1 - Arnlöv, Johan A1 - Arscott, Gillian M A1 - Attwood, Antony P A1 - Bandinelli, Stefania A1 - Barrett, Amy A1 - Bas, Isabelita N A1 - Bellis, Claire A1 - Bennett, Amanda J A1 - Berne, Christian A1 - Blagieva, Roza A1 - Blüher, Matthias A1 - Böhringer, Stefan A1 - Bonnycastle, Lori L A1 - Böttcher, Yvonne A1 - Boyd, Heather A A1 - 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Seufferlein, Thomas A1 - Shi, Jianxin A1 - Vernon Smith, Albert A1 - Smolonska, Joanna A1 - Stanton, Alice V A1 - Steinthorsdottir, Valgerdur A1 - Stirrups, Kathleen A1 - Stringham, Heather M A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Syvänen, Ann-Christine A1 - Tan, Sian-Tsung A1 - Tayo, Bamidele O A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tyrer, Jonathan P A1 - Uh, Hae-Won A1 - Vandenput, Liesbeth A1 - Verhulst, Frank C A1 - Vermeulen, Sita H A1 - Verweij, Niek A1 - Vonk, Judith M A1 - Waite, Lindsay L A1 - Warren, Helen R A1 - Waterworth, Dawn A1 - Weedon, Michael N A1 - Wilkens, Lynne R A1 - Willenborg, Christina A1 - Wilsgaard, Tom A1 - Wojczynski, Mary K A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zhang, Qunyuan A1 - Brennan, Eoin P A1 - Choi, Murim A1 - Dastani, Zari A1 - Drong, Alexander W A1 - Eriksson, Per A1 - Franco-Cereceda, Anders A1 - Gådin, Jesper R A1 - Gharavi, Ali G A1 - Goddard, Michael E A1 - Handsaker, Robert E A1 - Huang, Jinyan A1 - 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Crawford, Dana C A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Danesh, John A1 - de Faire, Ulf A1 - den Ruijter, Hester M A1 - Dominiczak, Anna F A1 - Erbel, Raimund A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Farrall, Martin A1 - Felix, Stephan B A1 - Ferrannini, Ele A1 - Ferrières, Jean A1 - Ford, Ian A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Gansevoort, Ron T A1 - Gejman, Pablo V A1 - Gieger, Christian A1 - Gottesman, Omri A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hall, Alistair S A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hicks, Andrew A A1 - Hindorff, Lucia A A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hovingh, G Kees A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hyppönen, Elina A1 - Illig, Thomas A1 - Jacobs, Kevin B A1 - Järvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Johansen, Berit A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Jula, Antti M A1 - Kaprio, Jaakko A1 - Kastelein, John J P A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kiemeney, Lambertus A A1 - Knekt, Paul A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Le Marchand, Loic A1 - Lehtimäki, Terho A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Marette, André A1 - Matise, Tara C A1 - McKenzie, Colin A A1 - McKnight, Barbara A1 - Moll, Frans L A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Murray, Jeffrey C A1 - Nelis, Mari A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Madden, Pamela A F A1 - Pasterkamp, Gerard A1 - Peden, John F A1 - Peters, Annette A1 - Postma, Dirkje S A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Rioux, John D A1 - Ritchie, Marylyn D A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sarzynski, Mark A A1 - Schunkert, Heribert A1 - Schwarz, Peter E H A1 - Sever, Peter A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tönjes, Anke A1 - Trégouët, David-Alexandre A1 - Tremblay, Angelo A1 - Tremoli, Elena A1 - Virtamo, Jarmo A1 - Vohl, Marie-Claude A1 - Völker, Uwe A1 - Waeber, Gerard A1 - Willemsen, Gonneke A1 - Witteman, Jacqueline C A1 - Zillikens, M Carola A1 - Adair, Linda S A1 - Amouyel, Philippe A1 - Asselbergs, Folkert W A1 - Assimes, Themistocles L A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Bornstein, Stefan R A1 - Bottinger, Erwin P A1 - Bouchard, Claude A1 - Cauchi, Stéphane A1 - Chambers, John C A1 - Chanock, Stephen J A1 - Cooper, Richard S A1 - de Bakker, Paul I W A1 - Dedoussis, George A1 - Ferrucci, Luigi A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Groop, Leif C A1 - Haiman, Christopher A A1 - Hamsten, Anders A1 - Hui, Jennie A1 - Hunter, David J A1 - Hveem, Kristian A1 - Kaplan, Robert C A1 - Kivimaki, Mika A1 - Kuh, Diana A1 - Laakso, Markku A1 - Liu, Yongmei A1 - Martin, Nicholas G A1 - März, Winfried A1 - Melbye, Mads A1 - Metspalu, Andres A1 - Moebus, Susanne A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pérusse, Louis A1 - Peters, Ulrike A1 - Power, Chris A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rivadeneira, Fernando A1 - Saaristo, Timo E A1 - Saleheen, Danish A1 - Sattar, Naveed A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Slagboom, P Eline A1 - Snieder, Harold A1 - Spector, Tim D A1 - Thorsteinsdottir, Unnur A1 - Stumvoll, Michael A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Walker, Mark A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Zanen, Pieter A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Heid, Iris M A1 - O'Connell, Jeffrey R A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Abecasis, Goncalo R A1 - Franke, Lude A1 - Frayling, Timothy M A1 - McCarthy, Mark I A1 - Visscher, Peter M A1 - Scherag, André A1 - Willer, Cristen J A1 - Boehnke, Michael A1 - Mohlke, Karen L A1 - Lindgren, Cecilia M A1 - Beckmann, Jacques S A1 - Barroso, Inês A1 - North, Kari E A1 - Ingelsson, Erik A1 - Hirschhorn, Joel N A1 - Loos, Ruth J F A1 - Speliotes, Elizabeth K KW - Adipogenesis KW - Adiposity KW - Age Factors KW - Body Mass Index KW - Continental Population Groups KW - Energy Metabolism KW - Europe KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glutamic Acid KW - Humans KW - Insulin KW - Male KW - Obesity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Synapses AB -

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

VL - 518 IS - 7538 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25673413?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis on five isolated populations identifies variants of the HLA-DOA gene associated with white wine liking. JF - Eur J Hum Genet Y1 - 2015 A1 - Pirastu, Nicola A1 - Kooyman, Maarten A1 - Traglia, Michela A1 - Robino, Antonietta A1 - Willems, Sara M A1 - Pistis, Giorgio A1 - Amin, Najaf A1 - Sala, Cinzia A1 - Karssen, Lennart C A1 - van Duijn, Cornelia M A1 - Toniolo, Daniela A1 - Gasparini, Paolo AB -

Wine is the most popular alcoholic beverage around the world and because of its importance in society has been widely studied. Understanding what drives its flavor has been a quest for decades but much is still unknown and will be determined at least in part by individual taste preferences. Recently studies in the genetics of taste have uncovered the role of different genes in the determination of food preferences giving new insight on its physiology. In this context we have performed a genome-wide association study on red and white wine liking using three isolated populations collected in Italy, and replicated our results on two additional populations coming from the Netherland and Central Asia for a total of 3885 samples. We have found a significant association (P=2.1 × 10(-8)) between white wine liking and rs9276975:C>T a polymorphism in the HLA-DOA gene encoding a non-canonical MHC II molecule, which regulates other MHC II molecules. The same association was also found with red wine liking (P=8.3 × 10(-6)). Sex-separated analysis have also revealed that the effect of HLA-DOA is twice as large in women as compared to men suggesting an interaction between this polymorphism and gender. Our results are one of the first examples of genome-wide association between liking of a commonly consumed food and gene variants. Moreover, our results suggest a role of the MHC system in the determination of food preferences opening new insight in this field in general.

VL - 23 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25758996?dopt=Abstract ER - TY - JOUR T1 - Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia. JF - Nat Genet Y1 - 2015 A1 - Noetzli, Leila A1 - Lo, Richard W A1 - Lee-Sherick, Alisa B A1 - Callaghan, Michael A1 - Noris, Patrizia A1 - Savoia, Anna A1 - Rajpurkar, Madhvi A1 - Jones, Kenneth A1 - Gowan, Katherine A1 - Balduini, Carlo L A1 - Pecci, Alessandro A1 - Gnan, Chiara A1 - De Rocco, Daniela A1 - Doubek, Michael A1 - Li, Ling A1 - Lu, Lily A1 - Leung, Richard A1 - Landolt-Marticorena, Carolina A1 - Hunger, Stephen A1 - Heller, Paula A1 - Gutierrez-Hartmann, Arthur A1 - Xiayuan, Liang A1 - Pluthero, Fred G A1 - Rowley, Jesse W A1 - Weyrich, Andrew S A1 - Kahr, Walter H A A1 - Porter, Christopher C A1 - Di Paola, Jorge KW - Adult KW - Child, Preschool KW - DNA Mutational Analysis KW - Erythrocytes, Abnormal KW - Exome KW - Female KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Germ-Line Mutation KW - HEK293 Cells KW - Hematologic Diseases KW - Humans KW - Male KW - Mutation, Missense KW - Pedigree KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma KW - Proto-Oncogene Proteins c-ets KW - Repressor Proteins KW - Thrombocytopenia AB -

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

VL - 47 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25807284?dopt=Abstract ER - TY - JOUR T1 - The Global Burden of Cancer 2013. JF - JAMA Oncol Y1 - 2015 A1 - Fitzmaurice, Christina A1 - Dicker, Daniel A1 - Pain, Amanda A1 - Hamavid, Hannah A1 - Moradi-Lakeh, Maziar A1 - MacIntyre, Michael F A1 - Allen, Christine A1 - Hansen, Gillian A1 - Woodbrook, Rachel A1 - Wolfe, Charles A1 - Hamadeh, Randah R A1 - Moore, Ami A1 - Werdecker, Andrea A1 - Gessner, Bradford D A1 - Te Ao, Braden A1 - McMahon, Brian A1 - Karimkhani, Chante A1 - Yu, Chuanhua A1 - Cooke, Graham S A1 - Schwebel, David C A1 - Carpenter, David O A1 - Pereira, David M A1 - Nash, Denis A1 - Kazi, Dhruv S A1 - De Leo, Diego A1 - Plass, Dietrich A1 - Ukwaja, Kingsley N A1 - Thurston, George D A1 - Yun Jin, Kim A1 - Simard, Edgar P A1 - Mills, Edward A1 - Park, Eun-Kee A1 - Catalá-López, Ferrán A1 - deVeber, Gabrielle A1 - Gotay, Carolyn A1 - Khan, Gulfaraz A1 - Hosgood, H Dean A1 - Santos, Itamar S A1 - Leasher, Janet L A1 - Singh, Jasvinder A1 - Leigh, James A1 - Jonas, Jost A1 - Sanabria, Juan A1 - Beardsley, Justin A1 - Jacobsen, Kathryn H A1 - Takahashi, Ken A1 - Franklin, Richard C A1 - Ronfani, Luca A1 - Montico, Marcella A1 - Naldi, Luigi A1 - Tonelli, Marcello A1 - Geleijnse, Johanna A1 - Petzold, Max A1 - Shrime, Mark G A1 - Younis, Mustafa A1 - Yonemoto, Naohiro A1 - Breitborde, Nicholas A1 - Yip, Paul A1 - Pourmalek, Farshad A1 - Lotufo, Paulo A A1 - Esteghamati, Alireza A1 - Hankey, Graeme J A1 - Ali, Raghib A1 - Lunevicius, Raimundas A1 - Malekzadeh, Reza A1 - Dellavalle, Robert A1 - Weintraub, Robert A1 - Lucas, Robyn A1 - Hay, Roderick A1 - Rojas-Rueda, David A1 - Westerman, Ronny A1 - Sepanlou, Sadaf G A1 - Nolte, Sandra A1 - Patten, Scott A1 - Weichenthal, Scott A1 - Abera, Semaw Ferede A1 - Fereshtehnejad, Seyed-Mohammad A1 - Shiue, Ivy A1 - Driscoll, Tim A1 - Vasankari, Tommi A1 - Alsharif, Ubai A1 - Rahimi-Movaghar, Vafa A1 - Vlassov, Vasiliy V A1 - Marcenes, W S A1 - Mekonnen, Wubegzier A1 - Melaku, Yohannes Adama A1 - Yano, Yuichiro A1 - Artaman, Al A1 - Campos, Ismael A1 - MacLachlan, Jennifer A1 - Mueller, Ulrich A1 - Kim, Daniel A1 - Trillini, Matias A1 - Eshrati, Babak A1 - Williams, Hywel C A1 - Shibuya, Kenji A1 - Dandona, Rakhi A1 - Murthy, Kinnari A1 - Cowie, Benjamin A1 - Amare, Azmeraw T A1 - Antonio, Carl Abelardo A1 - Castañeda-Orjuela, Carlos A1 - van Gool, Coen H A1 - Violante, Francesco A1 - Oh, In-Hwan A1 - Deribe, Kedede A1 - Soreide, Kjetil A1 - Knibbs, Luke A1 - Kereselidze, Maia A1 - Green, Mark A1 - Cárdenas, Rosario A1 - Roy, Nobhojit A1 - Tillman, Taavi A1 - Li, Yongmei A1 - Krueger, Hans A1 - Monasta, Lorenzo A1 - Dey, Subhojit A1 - Sheikhbahaei, Sara A1 - Hafezi-Nejad, Nima A1 - Kumar, G Anil A1 - Sreeramareddy, Chandrashekhar T A1 - Dandona, Lalit A1 - Wang, Haidong A1 - Vollset, Stein Emil A1 - Mokdad, Ali A1 - Salomon, Joshua A A1 - Lozano, Rafael A1 - Vos, Theo A1 - Forouzanfar, Mohammad A1 - Lopez, Alan A1 - Murray, Christopher A1 - Naghavi, Mohsen AB -

IMPORTANCE: Cancer is among the leading causes of death worldwide. Current estimates of cancer burden in individual countries and regions are necessary to inform local cancer control strategies.

OBJECTIVE: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 28 cancers in 188 countries by sex from 1990 to 2013.

EVIDENCE REVIEW: The general methodology of the Global Burden of Disease (GBD) 2013 study was used. Cancer registries were the source for cancer incidence data as well as mortality incidence (MI) ratios. Sources for cause of death data include vital registration system data, verbal autopsy studies, and other sources. The MI ratios were used to transform incidence data to mortality estimates and cause of death estimates to incidence estimates. Cancer prevalence was estimated using MI ratios as surrogates for survival data; YLDs were calculated by multiplying prevalence estimates with disability weights, which were derived from population-based surveys; YLLs were computed by multiplying the number of estimated cancer deaths at each age with a reference life expectancy; and DALYs were calculated as the sum of YLDs and YLLs.

FINDINGS: In 2013 there were 14.9 million incident cancer cases, 8.2 million deaths, and 196.3 million DALYs. Prostate cancer was the leading cause for cancer incidence (1.4 million) for men and breast cancer for women (1.8 million). Tracheal, bronchus, and lung (TBL) cancer was the leading cause for cancer death in men and women, with 1.6 million deaths. For men, TBL cancer was the leading cause of DALYs (24.9 million). For women, breast cancer was the leading cause of DALYs (13.1 million). Age-standardized incidence rates (ASIRs) per 100 000 and age-standardized death rates (ASDRs) per 100 000 for both sexes in 2013 were higher in developing vs developed countries for stomach cancer (ASIR, 17 vs 14; ASDR, 15 vs 11), liver cancer (ASIR, 15 vs 7; ASDR, 16 vs 7), esophageal cancer (ASIR, 9 vs 4; ASDR, 9 vs 4), cervical cancer (ASIR, 8 vs 5; ASDR, 4 vs 2), lip and oral cavity cancer (ASIR, 7 vs 6; ASDR, 2 vs 2), and nasopharyngeal cancer (ASIR, 1.5 vs 0.4; ASDR, 1.2 vs 0.3). Between 1990 and 2013, ASIRs for all cancers combined (except nonmelanoma skin cancer and Kaposi sarcoma) increased by more than 10% in 113 countries and decreased by more than 10% in 12 of 188 countries.

CONCLUSIONS AND RELEVANCE: Cancer poses a major threat to public health worldwide, and incidence rates have increased in most countries since 1990. The trend is a particular threat to developing nations with health systems that are ill-equipped to deal with complex and expensive cancer treatments. The annual update on the Global Burden of Cancer will provide all stakeholders with timely estimates to guide policy efforts in cancer prevention, screening, treatment, and palliation.

VL - 1 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26181261?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2015 A1 - Forouzanfar, Mohammad H A1 - Alexander, Lily A1 - Anderson, H Ross A1 - Bachman, Victoria F A1 - Biryukov, Stan A1 - Brauer, Michael A1 - Burnett, Richard A1 - Casey, Daniel A1 - Coates, Matthew M A1 - Cohen, Aaron A1 - Delwiche, Kristen A1 - Estep, Kara A1 - Frostad, Joseph J A1 - Astha, K C A1 - Kyu, Hmwe H A1 - Moradi-Lakeh, Maziar A1 - Ng, Marie A1 - Slepak, Erica Leigh A1 - Thomas, Bernadette A A1 - Wagner, Joseph A1 - Aasvang, Gunn Marit A1 - Abbafati, Cristiana A1 - Abbasoglu Ozgoren, Ayse A1 - Abd-Allah, Foad A1 - Abera, Semaw F A1 - Aboyans, Victor A1 - Abraham, Biju A1 - Abraham, Jerry Puthenpurakal A1 - Abubakar, Ibrahim A1 - Abu-Rmeileh, Niveen M E A1 - Aburto, Tania C A1 - Achoki, Tom A1 - Adelekan, Ademola A1 - Adofo, Koranteng A1 - Adou, Arsène K A1 - Adsuar, José C A1 - Afshin, Ashkan A1 - Agardh, Emilie E A1 - Al Khabouri, Mazin J A1 - Al Lami, Faris H A1 - Alam, Sayed Saidul A1 - Alasfoor, Deena A1 - Albittar, Mohammed I A1 - Alegretti, Miguel A A1 - Aleman, Alicia V A1 - Alemu, Zewdie A A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Ali, Mohammed K A1 - Alla, François A1 - Allebeck, Peter A1 - Allen, Peter J A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Ameh, Emmanuel A A1 - Ameli, Omid A1 - Amini, Heresh A1 - Ammar, Walid A1 - Anderson, Benjamin O A1 - Antonio, Carl Abelardo T A1 - Anwari, Palwasha A1 - Argeseanu Cunningham, Solveig A1 - Arnlöv, Johan A1 - Arsenijevic, Valentina S Arsic A1 - Artaman, Al A1 - Asghar, Rana J A1 - Assadi, Reza A1 - Atkins, Lydia S A1 - Atkinson, Charles A1 - Avila, Marco A A1 - Awuah, Baffour A1 - Badawi, Alaa A1 - Bahit, Maria C A1 - Bakfalouni, Talal A1 - Balakrishnan, Kalpana A1 - Balalla, Shivanthi A1 - Balu, Ravi Kumar A1 - Banerjee, Amitava A1 - Barber, Ryan M A1 - Barker-Collo, Suzanne L A1 - Barquera, Simon A1 - Barregard, Lars A1 - Barrero, Lope H A1 - Barrientos-Gutierrez, Tonatiuh A1 - Basto-Abreu, Ana C A1 - Basu, Arindam A1 - Basu, Sanjay A1 - Basulaiman, Mohammed O A1 - Batis Ruvalcaba, Carolina A1 - Beardsley, Justin A1 - Bedi, Neeraj A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Benjet, Corina A1 - Bennett, Derrick A A1 - Benzian, Habib A1 - Bernabe, Eduardo A1 - Beyene, Tariku J A1 - Bhala, Neeraj A1 - Bhalla, Ashish A1 - Bhutta, Zulfiqar A A1 - Bikbov, Boris A1 - Bin Abdulhak, Aref A A1 - Blore, Jed D A1 - Blyth, Fiona M A1 - Bohensky, Megan A A1 - Bora Başara, Berrak A1 - Borges, Guilherme A1 - Bornstein, Natan M A1 - Bose, Dipan A1 - Boufous, Soufiane A1 - Bourne, Rupert R A1 - Brainin, Michael A1 - Brazinova, Alexandra A1 - Breitborde, Nicholas J A1 - Brenner, Hermann A1 - Briggs, Adam D M A1 - Broday, David M A1 - Brooks, Peter M A1 - Bruce, Nigel G A1 - Brugha, Traolach S A1 - Brunekreef, Bert A1 - Buchbinder, Rachelle A1 - Bui, Linh N A1 - Bukhman, Gene A1 - Bulloch, Andrew G A1 - Burch, Michael A1 - Burney, Peter G J A1 - Campos-Nonato, Ismael R A1 - Campuzano, Julio C A1 - Cantoral, Alejandra J A1 - Caravanos, Jack A1 - Cárdenas, Rosario A1 - Cardis, Elisabeth A1 - Carpenter, David O A1 - Caso, Valeria A1 - Castañeda-Orjuela, Carlos A A1 - Castro, Ruben E A1 - Catalá-López, Ferrán A1 - Cavalleri, Fiorella A1 - Cavlin, Alanur A1 - Chadha, Vineet K A1 - Chang, Jung-Chen A1 - Charlson, Fiona J A1 - Chen, Honglei A1 - Chen, Wanqing A1 - Chen, Zhengming A1 - Chiang, Peggy P A1 - Chimed-Ochir, Odgerel A1 - Chowdhury, Rajiv A1 - Christophi, Costas A A1 - Chuang, Ting-Wu A1 - Chugh, Sumeet S A1 - Cirillo, Massimo A1 - Claßen, Thomas K D A1 - Colistro, Valentina A1 - Colomar, Mercedes A1 - Colquhoun, Samantha M A1 - Contreras, Alejandra G A1 - Cooper, Cyrus A1 - Cooperrider, Kimberly A1 - Cooper, Leslie T A1 - Coresh, Josef A1 - Courville, Karen J A1 - Criqui, Michael H A1 - Cuevas-Nasu, Lucia A1 - Damsere-Derry, James A1 - Danawi, Hadi A1 - Dandona, Lalit A1 - Dandona, Rakhi A1 - Dargan, Paul I A1 - Davis, Adrian A1 - Davitoiu, Dragos V A1 - Dayama, Anand A1 - de Castro, E Filipa A1 - De la Cruz-Góngora, Vanessa A1 - De Leo, Diego A1 - de Lima, Graça A1 - Degenhardt, Louisa A1 - del Pozo-Cruz, Borja A1 - Dellavalle, Robert P A1 - Deribe, Kebede A1 - Derrett, Sarah A1 - Des Jarlais, Don C A1 - Dessalegn, Muluken A1 - deVeber, Gabrielle A A1 - Devries, Karen M A1 - Dharmaratne, Samath D A1 - Dherani, Mukesh K A1 - Dicker, Daniel A1 - Ding, Eric L A1 - Dokova, Klara A1 - Dorsey, E Ray A1 - Driscoll, Tim R A1 - Duan, Leilei A1 - Durrani, Adnan M A1 - Ebel, Beth E A1 - Ellenbogen, Richard G A1 - Elshrek, Yousef M A1 - Endres, Matthias A1 - Ermakov, Sergey P A1 - Erskine, Holly E A1 - Eshrati, Babak A1 - Esteghamati, Alireza A1 - Fahimi, Saman A1 - Faraon, Emerito Jose A A1 - Farzadfar, Farshad A1 - Fay, Derek F J A1 - Feigin, Valery L A1 - Feigl, Andrea B A1 - Fereshtehnejad, Seyed-Mohammad A1 - Ferrari, Alize J A1 - Ferri, Cleusa P A1 - Flaxman, Abraham D A1 - Fleming, Thomas D A1 - Foigt, Nataliya A1 - Foreman, Kyle J A1 - Paleo, Urbano Fra A1 - Franklin, Richard C A1 - Gabbe, Belinda A1 - Gaffikin, Lynne A1 - Gakidou, Emmanuela A1 - Gamkrelidze, Amiran A1 - Gankpé, Fortuné G A1 - Gansevoort, Ron T A1 - García-Guerra, Francisco A A1 - Gasana, Evariste A1 - Geleijnse, Johanna M A1 - Gessner, Bradford D A1 - Gething, Pete A1 - Gibney, Katherine B A1 - Gillum, Richard F A1 - Ginawi, Ibrahim A M A1 - Giroud, Maurice A1 - Giussani, Giorgia A1 - Goenka, Shifalika A1 - Goginashvili, Ketevan A1 - Gomez Dantes, Hector A1 - Gona, Philimon A1 - Gonzalez de Cosio, Teresita A1 - González-Castell, Dinorah A1 - Gotay, Carolyn C A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Guerrant, Richard L A1 - Gugnani, Harish C A1 - Guillemin, Francis A1 - Gunnell, David A1 - Gupta, Rahul A1 - Gupta, Rajeev A1 - Gutiérrez, Reyna A A1 - Hafezi-Nejad, Nima A1 - Hagan, Holly A1 - Hagstromer, Maria A1 - Halasa, Yara A A1 - Hamadeh, Randah R A1 - Hammami, Mouhanad A1 - Hankey, Graeme J A1 - Hao, Yuantao A1 - Harb, Hilda L A1 - Haregu, Tilahun Nigatu A1 - Haro, Josep Maria A1 - Havmoeller, Rasmus A1 - Hay, Simon I A1 - Hedayati, Mohammad T A1 - 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BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.

METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.

FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.

INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.

FUNDING: Bill & Melinda Gates Foundation.

VL - 386 IS - 10010 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26364544?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition. JF - Lancet Y1 - 2015 A1 - Murray, Christopher J L A1 - Barber, Ryan M A1 - Foreman, Kyle J A1 - Abbasoglu Ozgoren, Ayse A1 - Abd-Allah, Foad A1 - Abera, Semaw F A1 - Aboyans, Victor A1 - Abraham, Jerry P A1 - Abubakar, Ibrahim A1 - Abu-Raddad, Laith J A1 - Abu-Rmeileh, Niveen M A1 - Achoki, Tom A1 - Ackerman, Ilana N A1 - Ademi, Zanfina A1 - Adou, Arsène K A1 - Adsuar, José C A1 - Afshin, Ashkan A1 - Agardh, Emilie E A1 - Alam, Sayed Saidul A1 - Alasfoor, Deena A1 - Albittar, Mohammed I A1 - Alegretti, Miguel A A1 - Alemu, Zewdie A A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Alla, François A1 - Allebeck, Peter A1 - AlMazroa, Mohammad A A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amare, Azmeraw T A1 - Ameh, Emmanuel A A1 - Amini, Heresh A1 - Ammar, Walid A1 - Anderson, H Ross A1 - Anderson, Benjamin O A1 - Antonio, Carl Abelardo T A1 - Anwari, Palwasha A1 - Arnlöv, Johan A1 - Arsic Arsenijevic, Valentina S A1 - Artaman, Al A1 - Asghar, Rana J A1 - 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Lotufo, Paulo A A1 - Lozano, Rafael A1 - Lucas, Robyn M A1 - Lunevicius, Raimundas A1 - Lyons, Ronan A A1 - Ma, Stefan A1 - MacIntyre, Michael F A1 - Mackay, Mark T A1 - Majdan, Marek A1 - Malekzadeh, Reza A1 - Marcenes, Wagner A1 - Margolis, David J A1 - Margono, Christopher A1 - Marzan, Melvin B A1 - Masci, Joseph R A1 - Mashal, Mohammad T A1 - Matzopoulos, Richard A1 - Mayosi, Bongani M A1 - Mazorodze, Tasara T A1 - Mcgill, Neil W A1 - McGrath, John J A1 - McKee, Martin A1 - McLain, Abigail A1 - Meaney, Peter A A1 - Medina, Catalina A1 - Mehndiratta, Man Mohan A1 - Mekonnen, Wubegzier A1 - Melaku, Yohannes A A1 - Meltzer, Michele A1 - Memish, Ziad A A1 - Mensah, George A A1 - Meretoja, Atte A1 - Mhimbira, Francis A A1 - Micha, Renata A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mitchell, Philip B A1 - Mock, Charles N A1 - Mohamed Ibrahim, Norlinah A1 - Mohammad, Karzan A A1 - Mokdad, Ali H A1 - Mola, Glen L D A1 - Monasta, Lorenzo A1 - Montañez Hernandez, Julio C A1 - Montico, Marcella A1 - Montine, Thomas J A1 - Mooney, Meghan D A1 - Moore, Ami R A1 - Moradi-Lakeh, Maziar A1 - Moran, Andrew E A1 - Mori, Rintaro A1 - Moschandreas, Joanna A1 - Moturi, Wilkister N A1 - Moyer, Madeline L A1 - Mozaffarian, Dariush A1 - Msemburi, William T A1 - Mueller, Ulrich O A1 - Mukaigawara, Mitsuru A1 - Mullany, Erin C A1 - Murdoch, Michele E A1 - Murray, Joseph A1 - Murthy, Kinnari S A1 - Naghavi, Mohsen A1 - Naheed, Aliya A1 - Naidoo, Kovin S A1 - Naldi, Luigi A1 - Nand, Devina A1 - Nangia, Vinay A1 - Narayan, K M Venkat A1 - Nejjari, Chakib A1 - Neupane, Sudan P A1 - Newton, Charles R A1 - Ng, Marie A1 - Ngalesoni, Frida N A1 - Nguyen, Grant A1 - Nisar, Muhammad I A1 - Nolte, Sandra A1 - Norheim, Ole F A1 - Norman, Rosana E A1 - Norrving, Bo A1 - Nyakarahuka, Luke A1 - Oh, In-Hwan A1 - Ohkubo, Takayoshi A1 - Ohno, Summer L A1 - Olusanya, Bolajoko O A1 - Opio, John Nelson A1 - Ortblad, Katrina A1 - Ortiz, Alberto A1 - Pain, Amanda W A1 - Pandian, Jeyaraj D A1 - Panelo, Carlo Irwin A A1 - Papachristou, Christina A1 - Park, Eun-Kee A1 - Park, Jae-Hyun A1 - Patten, Scott B A1 - Patton, George C A1 - Paul, Vinod K A1 - Pavlin, Boris I A1 - Pearce, Neil A1 - Pereira, David M A1 - Perez-Padilla, Rogelio A1 - Perez-Ruiz, Fernando A1 - Perico, Norberto A1 - Pervaiz, Aslam A1 - Pesudovs, Konrad A1 - Peterson, Carrie B A1 - Petzold, Max A1 - Phillips, Michael R A1 - Phillips, Bryan K A1 - Phillips, David E A1 - Piel, Frédéric B A1 - Plass, Dietrich A1 - Poenaru, Dan A1 - Polinder, Suzanne A1 - Pope, Daniel A1 - Popova, Svetlana A1 - Poulton, Richie G A1 - Pourmalek, Farshad A1 - Prabhakaran, Dorairaj A1 - Prasad, Noela M A1 - Pullan, Rachel L A1 - Qato, Dima M A1 - Quistberg, D Alex A1 - Rafay, Anwar A1 - Rahimi, Kazem A1 - Rahman, Sajjad U A1 - Raju, Murugesan A1 - Rana, Saleem M A1 - Razavi, Homie A1 - Reddy, K Srinath A1 - Refaat, Amany A1 - Remuzzi, Giuseppe A1 - Resnikoff, Serge A1 - Ribeiro, Antonio L A1 - Richardson, Lee A1 - Richardus, Jan Hendrik A1 - Roberts, D Allen A1 - 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Toyoshima, Hideaki A1 - Traebert, Jefferson A1 - Tran, Bach X A1 - Trillini, Matias A1 - Truelsen, Thomas A1 - Tsilimbaris, Miltiadis A1 - Tuzcu, Emin M A1 - Uchendu, Uche S A1 - Ukwaja, Kingsley N A1 - Undurraga, Eduardo A A1 - Uzun, Selen B A1 - Van Brakel, Wim H A1 - van de Vijver, Steven A1 - van Gool, Coen H A1 - van Os, Jim A1 - Vasankari, Tommi J A1 - Venketasubramanian, N A1 - Violante, Francesco S A1 - Vlassov, Vasiliy V A1 - Vollset, Stein Emil A1 - Wagner, Gregory R A1 - Wagner, Joseph A1 - Waller, Stephen G A1 - Wan, Xia A1 - Wang, Haidong A1 - Wang, JianLi A1 - Wang, Linhong A1 - Warouw, Tati S A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Wenzhi, Wang A1 - Werdecker, Andrea A1 - Westerman, Ronny A1 - Whiteford, Harvey A A1 - Wilkinson, James D A1 - Williams, Thomas N A1 - Wolfe, Charles D A1 - Wolock, Timothy M A1 - Woolf, Anthony D A1 - Wulf, Sarah A1 - Wurtz, Brittany A1 - Xu, Gelin A1 - Yan, Lijing L A1 - Yano, Yuichiro A1 - Ye, Pengpeng A1 - Yentür, Gökalp K A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa Z A1 - Yu, Chuanhua A1 - Zaki, Maysaa E A1 - Zhao, Yong A1 - Zheng, Yingfeng A1 - Zonies, David A1 - Zou, Xiaonong A1 - Salomon, Joshua A A1 - Lopez, Alan D A1 - Vos, Theo KW - Aged KW - Chronic Disease KW - Communicable Diseases KW - Female KW - Global Health KW - Health Transition KW - Humans KW - Life Expectancy KW - Male KW - Middle Aged KW - Mortality, Premature KW - Quality-Adjusted Life Years KW - Socioeconomic Factors KW - Wounds and Injuries AB -

BACKGROUND: The Global Burden of Disease Study 2013 (GBD 2013) aims to bring together all available epidemiological data using a coherent measurement framework, standardised estimation methods, and transparent data sources to enable comparisons of health loss over time and across causes, age-sex groups, and countries. The GBD can be used to generate summary measures such as disability-adjusted life-years (DALYs) and healthy life expectancy (HALE) that make possible comparative assessments of broad epidemiological patterns across countries and time. These summary measures can also be used to quantify the component of variation in epidemiology that is related to sociodemographic development.

METHODS: We used the published GBD 2013 data for age-specific mortality, years of life lost due to premature mortality (YLLs), and years lived with disability (YLDs) to calculate DALYs and HALE for 1990, 1995, 2000, 2005, 2010, and 2013 for 188 countries. We calculated HALE using the Sullivan method; 95% uncertainty intervals (UIs) represent uncertainty in age-specific death rates and YLDs per person for each country, age, sex, and year. We estimated DALYs for 306 causes for each country as the sum of YLLs and YLDs; 95% UIs represent uncertainty in YLL and YLD rates. We quantified patterns of the epidemiological transition with a composite indicator of sociodemographic status, which we constructed from income per person, average years of schooling after age 15 years, and the total fertility rate and mean age of the population. We applied hierarchical regression to DALY rates by cause across countries to decompose variance related to the sociodemographic status variable, country, and time.

FINDINGS: Worldwide, from 1990 to 2013, life expectancy at birth rose by 6·2 years (95% UI 5·6-6·6), from 65·3 years (65·0-65·6) in 1990 to 71·5 years (71·0-71·9) in 2013, HALE at birth rose by 5·4 years (4·9-5·8), from 56·9 years (54·5-59·1) to 62·3 years (59·7-64·8), total DALYs fell by 3·6% (0·3-7·4), and age-standardised DALY rates per 100 000 people fell by 26·7% (24·6-29·1). For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers, crude rates, and age-standardised rates have all declined between 1990 and 2013, whereas for non-communicable diseases, global DALYs have been increasing, DALY rates have remained nearly constant, and age-standardised DALY rates declined during the same period. From 2005 to 2013, the number of DALYs increased for most specific non-communicable diseases, including cardiovascular diseases and neoplasms, in addition to dengue, food-borne trematodes, and leishmaniasis; DALYs decreased for nearly all other causes. By 2013, the five leading causes of DALYs were ischaemic heart disease, lower respiratory infections, cerebrovascular disease, low back and neck pain, and road injuries. Sociodemographic status explained more than 50% of the variance between countries and over time for diarrhoea, lower respiratory infections, and other common infectious diseases; maternal disorders; neonatal disorders; nutritional deficiencies; other communicable, maternal, neonatal, and nutritional diseases; musculoskeletal disorders; and other non-communicable diseases. However, sociodemographic status explained less than 10% of the variance in DALY rates for cardiovascular diseases; chronic respiratory diseases; cirrhosis; diabetes, urogenital, blood, and endocrine diseases; unintentional injuries; and self-harm and interpersonal violence. Predictably, increased sociodemographic status was associated with a shift in burden from YLLs to YLDs, driven by declines in YLLs and increases in YLDs from musculoskeletal disorders, neurological disorders, and mental and substance use disorders. In most country-specific estimates, the increase in life expectancy was greater than that in HALE. Leading causes of DALYs are highly variable across countries.

INTERPRETATION: Global health is improving. Population growth and ageing have driven up numbers of DALYs, but crude rates have remained relatively constant, showing that progress in health does not mean fewer demands on health systems. The notion of an epidemiological transition--in which increasing sociodemographic status brings structured change in disease burden--is useful, but there is tremendous variation in burden of disease that is not associated with sociodemographic status. This further underscores the need for country-specific assessments of DALYs and HALE to appropriately inform health policy decisions and attendant actions.

FUNDING: Bill & Melinda Gates Foundation.

VL - 386 IS - 10009 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26321261?dopt=Abstract ER - TY - JOUR T1 - Hysteroscopic chasing for endometrial cancer in a low-risk population: risks of overinvestigation. JF - Arch Gynecol Obstet Y1 - 2015 A1 - Scrimin, Federica A1 - Wiesenfeld, Uri A1 - Galati, Emanuele F A1 - Monasta, Lorenzo A1 - Ricci, Giuseppe AB -

PURPOSE: To evaluate the appropriateness of the indications for hysteroscopy done, in fertile and postmenopausal women, for the detection of endometrial cancer.

METHODS: A retrospective analysis of 2673 consecutive women who underwent office hysteroscopy chasing for endometrial cancer between January 2012 and June 2014. According to their medical history only low-risk women entered the study.

RESULTS: A total of 1070 patients entered the study. The main outcome measure was the appropriateness of the indications for hysteroscopy. Appropriateness was assessed on the basis of guidelines of scientific societies and histologic report. According to the algorithm developed for appropriateness, 44 % of procedures resulted in being inappropriate. In reproductive-aged women 57 % of hysteroscopies were inappropriate. In postmenopausal women inappropriate hysteroscopies were 45 %. In reproductive-aged women, the reasons for inappropriateness were: absence of abnormal uterine bleeding (AUB) or AUB without a trial of progestin therapy. In postmenopausal women, the reasons for inappropriateness were: ultrasound report of endometrial thickening or polyp without bleeding.

CONCLUSIONS: Hysteroscopy is often recommended for inappropriate indications. More evidence is needed to identify the risks of overinvestigation, overdiagnosis, and related overtreatment and to better identify the threshold beyond which benefits are likely to outweigh harms.

U1 - http://www.ncbi.nlm.nih.gov/pubmed/26315472?dopt=Abstract ER - TY - JOUR T1 - Identification of a novel frameshift mutation in the EDAR gene causing autosomal dominant hypohidrotic ectodermal dysplasia. JF - J Eur Acad Dermatol Venereol Y1 - 2015 A1 - Callea, M A1 - Willoughby, C E A1 - Nieminen, P A1 - Di Stazio, M A1 - Bellacchio, E A1 - Giglio, S A1 - Sani, I A1 - Vinciguerra, A A1 - Maglione, M A1 - Tadini, G A1 - Clarich, G VL - 29 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24641098?dopt=Abstract ER - TY - JOUR T1 - Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. JF - Nat Commun Y1 - 2015 A1 - Huang, Jie A1 - Howie, Bryan A1 - McCarthy, Shane A1 - Memari, Yasin A1 - Walter, Klaudia A1 - Min, Josine L A1 - Danecek, Petr A1 - Malerba, Giovanni A1 - Trabetti, Elisabetta A1 - Zheng, Hou-Feng A1 - Gambaro, Giovanni A1 - Richards, J Brent A1 - Durbin, Richard A1 - Timpson, Nicholas J A1 - Marchini, Jonathan A1 - Soranzo, Nicole AB -

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26368830?dopt=Abstract ER - TY - JOUR T1 - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. 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Barbieri, Caterina A1 - Beckmann, Matthias W A1 - Beeghly-Fadiel, Alicia A1 - Benitez, Javier A1 - Bernstein, Leslie A1 - Bielinski, Suzette J A1 - Blomqvist, Carl A1 - Boerwinkle, Eric A1 - Bogdanova, Natalia V A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Borresen-Dale, Anne-Lise A1 - Boutin, Thibaud S A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Brüning, Thomas A1 - Burwinkel, Barbara A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chapman, J Ross A1 - Chen, Yii-Der Ida A1 - Chenevix-Trench, Georgia A1 - Couch, Fergus J A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - Darabi, Hatef A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dörk, Thilo A1 - Dos-Santos-Silva, Isabel A1 - Dunning, Alison M A1 - Eicher, John D A1 - Fasching, Peter A A1 - Faul, Jessica D A1 - Figueroa, Jonine A1 - Flesch-Janys, Dieter A1 - Gandin, Ilaria A1 - Garcia, Melissa E A1 - García-Closas, Montserrat A1 - Giles, Graham G A1 - Girotto, Giorgia G A1 - Goldberg, Mark S A1 - González-Neira, Anna A1 - Goodarzi, Mark O A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Guenel, Pascal A1 - Guo, Xiuqing A1 - Haiman, Christopher A A1 - Hall, Per A1 - Hamann, Ute A1 - Henderson, Brian E A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank B A1 - Huang, Jinyan A1 - Humphreys, Keith A1 - Hunter, David J A1 - Jakubowska, Anna A1 - Jones, Samuel E A1 - Kabisch, Maria A1 - Karasik, David A1 - Knight, Julia A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Kosma, Veli-Matti A1 - Kriebel, Jennifer A1 - Kristensen, Vessela A1 - Lambrechts, Diether A1 - Langenberg, Claudia A1 - Li, Jingmei A1 - Li, Xin A1 - Lindström, Sara A1 - Liu, Yongmei A1 - Luan, Jian'an A1 - Lubinski, Jan A1 - Mägi, Reedik A1 - Mannermaa, Arto A1 - Manz, Judith A1 - Margolin, Sara A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Masciullo, Corrado A1 - Meindl, Alfons A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Milne, Roger L A1 - Müller-Nurasyid, Martina A1 - Nalls, Michael A1 - Neale, Benjamin M A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Newman, Anne B A1 - Nordestgaard, Børge G A1 - Olson, Janet E A1 - Padmanabhan, Sandosh A1 - Peterlongo, Paolo A1 - Peters, Ulrike A1 - Petersmann, Astrid A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Pirastu, Nicola N A1 - Pirie, Ailith A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Raffel, Leslie J A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Rudolph, Anja A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schmidt, Frank A1 - Schmutzler, Rita K A1 - Schoemaker, Minouk J A1 - Scott, Robert A A1 - Seynaeve, Caroline M A1 - Simard, Jacques A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Stöckl, Doris A1 - Strauch, Konstantin A1 - Swerdlow, Anthony A1 - Taylor, Kent D A1 - Thorsteinsdottir, Unnur A1 - Toland, Amanda E A1 - Tomlinson, Ian A1 - Truong, Therese A1 - Tryggvadottir, Laufey A1 - Turner, Stephen T A1 - Vozzi, Diego A1 - Wang, Qin A1 - Wellons, Melissa A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce B H R A1 - Wright, Alan F A1 - Yannoukakos, Drakoulis A1 - Zemunik, Tatijana A1 - Zheng, Wei A1 - Zygmunt, Marek A1 - Bergmann, Sven A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Ferrucci, Luigi A1 - Montgomery, Grant W A1 - Gudnason, Vilmundur A1 - Spector, Tim D A1 - van Duijn, Cornelia M A1 - Alizadeh, Behrooz Z A1 - Ciullo, Marina A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Gasparini, Paolo P A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Kardia, Sharon L R A1 - Kraft, Peter A1 - McKnight, Barbara A1 - Metspalu, Andres A1 - Morrison, Alanna C A1 - Reiner, Alex P A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Yerges-Armstrong, Laura M A1 - Price, Alkes L A1 - Stefansson, Kari A1 - Visser, Jenny A A1 - Ong, Ken K A1 - Chang-Claude, Jenny A1 - Murabito, Joanne M A1 - Perry, John R B A1 - Murray, Anna AB -

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract ER - TY - JOUR T1 - MID2 can substitute for MID1 and control exocytosis of lytic granules in cytotoxic T cells. JF - APMIS Y1 - 2015 A1 - Boding, Lasse A1 - Hansen, Ann K A1 - Meroni, Germana A1 - Levring, Trine B A1 - Woetmann, Anders A1 - Ødum, Niels A1 - Bonefeld, Charlotte M A1 - Geisler, Carsten KW - Animals KW - Cytoplasmic Granules KW - Exocytosis KW - Interferon-gamma KW - Mice KW - Mice, Inbred C57BL KW - Mice, Knockout KW - Microtubule-Associated Proteins KW - Proteins KW - T-Lymphocytes, Cytotoxic KW - Transcription Factors KW - Up-Regulation AB -

We have recently shown that the E3 ubiquitin ligase midline 1 (MID1) is upregulated in murine cytotoxic lymphocytes (CTL), where it controls exocytosis of lytic granules and the killing capacity. Accordingly, CTL from MID1 knock-out (MID1(-/-)) mice have a 25-30% reduction in exocytosis of lytic granules and cytotoxicity compared to CTL from wild-type (WT) mice. We wondered why the MID1 gene knock-out did not affect exocytosis and cytotoxicity more severely and speculated whether MID2, a close homologue of MID1, might partially compensate for the loss of MID1 in MID1(-/-) CTL. Here, we showed that MID2, like MID1, is upregulated in activated murine T cells. Furthermore, MID1(-/-) CTL upregulated MID2 two-twenty-fold stronger than CTL from WT mice, suggesting that MID2 might compensate for MID1. In agreement, transfection of MID2 into MID1(-/-) CTL completely rescued exocytosis of lytic granules in MID1(-/-) CTL, and vice versa, knock-down of MID2 inhibited exocytosis of lytic granules in both WT and MID1(-/-) CTL, demonstrating that both MID1 and MID2 play a central role in the regulation of granule exocytosis and that functional redundancy exists between MID1 and MID2 in CTL.

VL - 123 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25924778?dopt=Abstract ER - TY - JOUR T1 - Modulation of genetic associations with serum urate levels by body-mass-index in humans. JF - PLoS One Y1 - 2015 A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Mangino, Massimo A1 - Kapur, Karen A1 - Johnson, Toby A1 - Kutalik, Zoltán A1 - Pirastu, Nicola A1 - Pistis, Giorgio A1 - Lopez, Lorna M A1 - Haller, Toomas A1 - Salo, Perttu A1 - Goel, Anuj A1 - Li, Man A1 - Tanaka, Toshiko A1 - Dehghan, Abbas A1 - Ruggiero, Daniela A1 - Malerba, Giovanni A1 - Smith, Albert V A1 - Nolte, Ilja M A1 - Portas, Laura A1 - Phipps-Green, Amanda A1 - Boteva, Lora A1 - Navarro, Pau A1 - Johansson, Åsa A1 - Hicks, Andrew A A1 - Polasek, Ozren A1 - Esko, Tõnu A1 - Peden, John F A1 - Harris, Sarah E A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Tenesa, Albert A1 - Tin, Adrienne A1 - Mihailov, Evelin A1 - Grotevendt, Anne A1 - Gislason, Gauti K A1 - Coresh, Josef A1 - d'Adamo, Pio A1 - Ulivi, Sheila A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Campbell, Susan A1 - Kolcic, Ivana A1 - Fisher, Krista A1 - Viigimaa, Margus A1 - Metter, Jeffrey E A1 - Masciullo, Corrado A1 - Trabetti, Elisabetta A1 - Bombieri, Cristina A1 - Sorice, Rossella A1 - Döring, Angela A1 - Reischl, Eva A1 - Strauch, Konstantin A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Dalbeth, Nicola A1 - Stamp, Lisa A1 - Smit, Johannes H A1 - Kirin, Mirna A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Jula, Antti A1 - Salomaa, Veikko A1 - Sala, Cinzia A1 - Hengstenberg, Christian A1 - Burnier, Michel A1 - Mägi, Reedik A1 - Klopp, Norman A1 - Kloiber, Stefan A1 - Schipf, Sabine A1 - Ripatti, Samuli A1 - Cabras, Stefano A1 - Soranzo, Nicole A1 - Homuth, Georg A1 - Nutile, Teresa A1 - Munroe, Patricia B A1 - Hastie, Nicholas A1 - Campbell, Harry A1 - Rudan, Igor A1 - Cabrera, Claudia A1 - Haley, Chris A1 - Franco, Oscar H A1 - Merriman, Tony R A1 - Gudnason, Vilmundur A1 - Pirastu, Mario A1 - Penninx, Brenda W A1 - Snieder, Harold A1 - Metspalu, Andres A1 - Ciullo, Marina A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Dunlop, Malcolm G A1 - Wilson, James F A1 - Gasparini, Paolo A1 - Gyllensten, Ulf A1 - Spector, Tim D A1 - Wright, Alan F A1 - Hayward, Caroline A1 - Watkins, Hugh A1 - Perola, Markus A1 - Bochud, Murielle A1 - Kao, W H Linda A1 - Caulfield, Mark A1 - Toniolo, Daniela A1 - Völzke, Henry A1 - Gieger, Christian A1 - Köttgen, Anna A1 - Vitart, Veronique AB -

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

VL - 10 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25811787?dopt=Abstract ER - TY - JOUR T1 - Multicohort analysis of the maternal age effect on recombination. JF - Nat Commun Y1 - 2015 A1 - Martin, Hilary C A1 - Christ, Ryan A1 - Hussin, Julie G A1 - O'Connell, Jared A1 - Gordon, Scott A1 - Mbarek, Hamdi A1 - Hottenga, Jouke-Jan A1 - McAloney, Kerrie A1 - Willemsen, Gonnecke A1 - Gasparini, Paolo A1 - Pirastu, Nicola A1 - Montgomery, Grant W A1 - Navarro, Pau A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Vitart, Veronique A1 - Wilson, James F A1 - Marchini, Jonathan A1 - Boomsma, Dorret I A1 - Martin, Nicholas G A1 - Donnelly, Peter AB -

Several studies have reported that the number of crossovers increases with maternal age in humans, but others have found the opposite. Resolving the true effect has implications for understanding the maternal age effect on aneuploidies. Here, we revisit this question in the largest sample to date using single nucleotide polymorphism (SNP)-chip data, comprising over 6,000 meioses from nine cohorts. We develop and fit a hierarchical model to allow for differences between cohorts and between mothers. We estimate that over 10 years, the expected number of maternal crossovers increases by 2.1% (95% credible interval (0.98%, 3.3%)). Our results are not consistent with the larger positive and negative effects previously reported in smaller cohorts. We see heterogeneity between cohorts that is likely due to chance effects in smaller samples, or possibly to confounders, emphasizing that care should be taken when interpreting results from any specific cohort about the effect of maternal age on recombination.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26242864?dopt=Abstract ER - TY - JOUR T1 - New genetic loci link adipose and insulin biology to body fat distribution. JF - Nature Y1 - 2015 A1 - Shungin, Dmitry A1 - Winkler, Thomas W A1 - Croteau-Chonka, Damien C A1 - Ferreira, Teresa A1 - Locke, Adam E A1 - Mägi, Reedik A1 - Strawbridge, Rona J A1 - Pers, Tune H A1 - Fischer, Krista A1 - Justice, Anne E A1 - Workalemahu, Tsegaselassie A1 - Wu, Joseph M W A1 - Buchkovich, Martin L A1 - Heard-Costa, Nancy L A1 - Roman, Tamara S A1 - Drong, Alexander W A1 - Song, Ci A1 - Gustafsson, Stefan A1 - Day, Felix R A1 - Esko, Tõnu A1 - Fall, Tove A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Randall, Joshua C A1 - Scherag, André A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - Chen, Jin A1 - Fehrmann, Rudolf A1 - Karjalainen, Juha A1 - Kahali, Bratati A1 - Liu, Ching-Ti A1 - Schmidt, Ellen M A1 - Absher, Devin A1 - Amin, Najaf A1 - Anderson, Denise A1 - Beekman, Marian A1 - Bragg-Gresham, Jennifer L A1 - Buyske, Steven A1 - Demirkan, Ayse A1 - Ehret, Georg B A1 - Feitosa, Mary F A1 - Goel, Anuj A1 - Jackson, Anne U A1 - Johnson, Toby A1 - Kleber, Marcus E A1 - Kristiansson, Kati A1 - Mangino, Massimo A1 - Mateo Leach, Irene A1 - Medina-Gomez, Carolina A1 - Palmer, Cameron D A1 - Pasko, Dorota A1 - Pechlivanis, Sonali A1 - Peters, Marjolein J A1 - Prokopenko, Inga A1 - Stančáková, Alena A1 - Ju Sung, Yun A1 - Tanaka, Toshiko A1 - Teumer, Alexander A1 - Van Vliet-Ostaptchouk, Jana V A1 - Yengo, Loic A1 - Zhang, Weihua A1 - Albrecht, Eva A1 - Arnlöv, Johan A1 - Arscott, Gillian M A1 - Bandinelli, Stefania A1 - Barrett, Amy A1 - Bellis, Claire A1 - Bennett, Amanda J A1 - Berne, Christian A1 - Blüher, Matthias A1 - Böhringer, Stefan A1 - Bonnet, Fabrice A1 - Böttcher, Yvonne A1 - Bruinenberg, Marcel A1 - Carba, Delia B A1 - Caspersen, Ida H A1 - Clarke, Robert A1 - Daw, E Warwick A1 - Deelen, Joris A1 - Deelman, Ewa A1 - Delgado, Graciela A1 - Doney, Alex S F A1 - Eklund, Niina A1 - Erdos, Michael R A1 - Estrada, Karol A1 - Eury, Elodie A1 - Friedrich, Nele A1 - Garcia, Melissa E A1 - Giedraitis, Vilmantas A1 - Gigante, Bruna A1 - Go, Alan S A1 - Golay, Alain A1 - Grallert, Harald A1 - Grammer, Tanja B A1 - Gräßler, Jürgen A1 - Grewal, Jagvir A1 - Groves, Christopher J A1 - Haller, Toomas A1 - Hallmans, Goran A1 - Hartman, Catharina A A1 - Hassinen, Maija A1 - Hayward, Caroline A1 - Heikkilä, Kauko A1 - Herzig, Karl-Heinz A1 - Helmer, Quinta A1 - Hillege, Hans L A1 - Holmen, Oddgeir A1 - Hunt, Steven C A1 - Isaacs, Aaron A1 - Ittermann, Till A1 - James, Alan L A1 - Johansson, Ingegerd A1 - Juliusdottir, Thorhildur A1 - Kalafati, Ioanna-Panagiota A1 - Kinnunen, Leena A1 - Koenig, Wolfgang A1 - Kooner, Ishminder K A1 - Kratzer, Wolfgang A1 - Lamina, Claudia A1 - Leander, Karin A1 - Lee, Nanette R A1 - Lichtner, Peter A1 - Lind, Lars A1 - Lindström, Jaana A1 - Lobbens, Stéphane A1 - Lorentzon, Mattias A1 - Mach, François A1 - Magnusson, Patrik K E A1 - Mahajan, Anubha A1 - McArdle, Wendy L A1 - Menni, Cristina A1 - Merger, Sigrun A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Mills, Rebecca A1 - Moayyeri, Alireza A1 - Monda, Keri L A1 - Mooijaart, Simon P A1 - Mühleisen, Thomas W A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nalls, Michael A A1 - Narisu, Narisu A1 - Glorioso, Nicola A1 - Nolte, Ilja M A1 - Olden, Matthias A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Ried, Janina S A1 - Robertson, Neil R A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scharnagl, Hubert A1 - Scholtens, Salome A1 - Sennblad, Bengt A1 - Seufferlein, Thomas A1 - Sitlani, Colleen M A1 - Vernon Smith, Albert A1 - Stirrups, Kathleen A1 - Stringham, Heather M A1 - Sundström, Johan A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Syvänen, Ann-Christine A1 - Tayo, Bamidele O A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tomaschitz, Andreas A1 - Troffa, Chiara A1 - van Oort, Floor V A A1 - Verweij, Niek A1 - Vonk, Judith M A1 - Waite, Lindsay L A1 - Wennauer, Roman A1 - Wilsgaard, Tom A1 - Wojczynski, Mary K A1 - Wong, Andrew A1 - Zhang, Qunyuan A1 - Hua Zhao, Jing A1 - Brennan, Eoin P A1 - Choi, Murim A1 - Eriksson, Per A1 - Folkersen, Lasse A1 - Franco-Cereceda, Anders A1 - Gharavi, Ali G A1 - Hedman, Åsa K A1 - Hivert, Marie-France A1 - Huang, Jinyan A1 - Kanoni, Stavroula A1 - Karpe, Fredrik A1 - Keildson, Sarah A1 - Kiryluk, Krzysztof A1 - Liang, Liming A1 - Lifton, Richard P A1 - Ma, Baoshan A1 - McKnight, Amy J A1 - McPherson, Ruth A1 - Metspalu, Andres A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Montgomery, Grant W A1 - Murabito, Joanne M A1 - Nicholson, George A1 - Nyholt, Dale R A1 - Olsson, Christian A1 - Perry, John R B A1 - Reinmaa, Eva A1 - Salem, Rany M A1 - Sandholm, Niina A1 - Schadt, Eric E A1 - Scott, Robert A A1 - Stolk, Lisette A1 - Vallejo, Edgar E A1 - Westra, Harm-Jan A1 - Zondervan, Krina T A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Bakker, Stephan J L A1 - Beilby, John A1 - Bergman, Richard N A1 - Blangero, John A1 - Brown, Morris J A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chines, Peter S A1 - Claudi-Boehm, Simone A1 - Collins, Francis S A1 - Crawford, Dana C A1 - Danesh, John A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Dörr, Marcus A1 - Erbel, Raimund A1 - Eriksson, Johan G A1 - Farrall, Martin A1 - Ferrannini, Ele A1 - Ferrières, Jean A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Gansevoort, Ron T A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - Haiman, Christopher A A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Heliövaara, Markku A1 - Hicks, Andrew A A1 - Hingorani, Aroon D A1 - Hoffmann, Wolfgang A1 - Hofman, Albert A1 - Homuth, Georg A1 - Humphries, Steve E A1 - Hyppönen, Elina A1 - Illig, Thomas A1 - Järvelin, Marjo-Riitta A1 - Johansen, Berit A1 - Jousilahti, Pekka A1 - Jula, Antti M A1 - Kaprio, Jaakko A1 - Kee, Frank A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Le Marchand, Loic A1 - Lehtimäki, Terho A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Marette, André A1 - Matise, Tara C A1 - McKenzie, Colin A A1 - McKnight, Barbara A1 - Musk, Arthur W A1 - Möhlenkamp, Stefan A1 - Morris, Andrew D A1 - Nelis, Mari A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Palmer, Lyle J A1 - Penninx, Brenda W A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Ritchie, Marylyn D A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sarzynski, Mark A A1 - Schwarz, Peter E H A1 - Shuldiner, Alan R A1 - Staessen, Jan A A1 - Steinthorsdottir, Valgerdur A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Tönjes, Anke A1 - Tremblay, Angelo A1 - Tremoli, Elena A1 - Vohl, Marie-Claude A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Adair, Linda S A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Bornstein, Stefan R A1 - Bouchard, Claude A1 - Cauchi, Stéphane A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Cooper, Richard S A1 - Dedoussis, George A1 - Ferrucci, Luigi A1 - Froguel, Philippe A1 - Grabe, Hans-Jörgen A1 - Hamsten, Anders A1 - Hui, Jennie A1 - Hveem, Kristian A1 - Jöckel, Karl-Heinz A1 - Kivimaki, Mika A1 - Kuh, Diana A1 - Laakso, Markku A1 - Liu, Yongmei A1 - März, Winfried A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Pedersen, Nancy L A1 - Perola, Markus A1 - Pérusse, Louis A1 - Peters, Ulrike A1 - Power, Chris A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Rivadeneira, Fernando A1 - Saaristo, Timo E A1 - Saleheen, Danish A1 - Sinisalo, Juha A1 - Slagboom, P Eline A1 - Snieder, Harold A1 - Spector, Tim D A1 - Thorsteinsdottir, Unnur A1 - Stumvoll, Michael A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Veronesi, Giovanni A1 - Walker, Mark A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wichmann, H-Erich A1 - Abecasis, Goncalo R A1 - Assimes, Themistocles L A1 - Berndt, Sonja I A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Franke, Lude A1 - Frayling, Timothy M A1 - Groop, Leif C A1 - Hunter, David J A1 - Kaplan, Robert C A1 - O'Connell, Jeffrey R A1 - Qi, Lu A1 - Schlessinger, David A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Willer, Cristen J A1 - Visscher, Peter M A1 - Yang, Jian A1 - Hirschhorn, Joel N A1 - Zillikens, M Carola A1 - McCarthy, Mark I A1 - Speliotes, Elizabeth K A1 - North, Kari E A1 - Fox, Caroline S A1 - Barroso, Inês A1 - Franks, Paul W A1 - Ingelsson, Erik A1 - Heid, Iris M A1 - Loos, Ruth J F A1 - Cupples, L Adrienne A1 - Morris, Andrew P A1 - Lindgren, Cecilia M A1 - Mohlke, Karen L KW - Adipocytes KW - Adipogenesis KW - Adipose Tissue KW - Age Factors KW - Body Fat Distribution KW - Body Mass Index KW - Continental Population Groups KW - Epigenesis, Genetic KW - Europe KW - Female KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Insulin KW - Insulin Resistance KW - Male KW - Models, Biological KW - Neovascularization, Physiologic KW - Obesity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Sex Characteristics KW - Transcription, Genetic KW - Waist-Hip Ratio AB -

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

VL - 518 IS - 7538 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25673412?dopt=Abstract ER - TY - JOUR T1 - Population genetic differentiation of height and body mass index across Europe. JF - Nat Genet Y1 - 2015 A1 - Robinson, Matthew R A1 - Hemani, Gibran A1 - Medina-Gomez, Carolina A1 - Mezzavilla, Massimo A1 - Esko, Tõnu A1 - Shakhbazov, Konstantin A1 - Powell, Joseph E A1 - Vinkhuyzen, Anna A1 - Berndt, Sonja I A1 - Gustafsson, Stefan A1 - Justice, Anne E A1 - Kahali, Bratati A1 - Locke, Adam E A1 - Pers, Tune H A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - van Rheenen, Wouter A1 - Andreassen, Ole A A1 - Gasparini, Paolo A1 - Metspalu, Andres A1 - Berg, Leonard H van den A1 - Veldink, Jan H A1 - Rivadeneira, Fernando A1 - Werge, Thomas M A1 - Abecasis, Goncalo R A1 - Boomsma, Dorret I A1 - Chasman, Daniel I A1 - de Geus, Eco J C A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Hottenga, Jouke Jan A1 - Ingelsson, Erik A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - North, Kari E A1 - Pedersen, Nancy L A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Goddard, Michael E A1 - Yang, Jian A1 - Visscher, Peter M AB -

Across-nation differences in the mean values for complex traits are common, but the reasons for these differences are unknown. Here we find that many independent loci contribute to population genetic differences in height and body mass index (BMI) in 9,416 individuals across 14 European countries. Using discovery data on over 250,000 individuals and unbiased effect size estimates from 17,500 sibling pairs, we estimate that 24% (95% credible interval (CI) = 9%, 41%) and 8% (95% CI = 4%, 16%) of the captured additive genetic variance for height and BMI, respectively, reflect population genetic differences. Population genetic divergence differed significantly from that in a null model (height, P < 3.94 × 10(-8); BMI, P < 5.95 × 10(-4)), and we find an among-population genetic correlation for tall and slender individuals (r = -0.80, 95% CI = -0.95, -0.60), consistent with correlated selection for both phenotypes. Observed differences in height among populations reflected the predicted genetic means (r = 0.51; P < 0.001), but environmental differences across Europe masked genetic differentiation for BMI (P < 0.58).

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26366552?dopt=Abstract ER - TY - JOUR T1 - Rare coding variants and X-linked loci associated with age at menarche. JF - Nat Commun Y1 - 2015 A1 - Lunetta, Kathryn L A1 - Day, Felix R A1 - Sulem, Patrick A1 - Ruth, Katherine S A1 - Tung, Joyce Y A1 - Hinds, David A A1 - Esko, Tõnu A1 - Elks, Cathy E A1 - Altmaier, Elisabeth A1 - He, Chunyan A1 - Huffman, Jennifer E A1 - Mihailov, Evelin A1 - Porcu, Eleonora A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Schick, Ursula M A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Traglia, Michela A1 - Wang, Carol A A1 - Yerges-Armstrong, Laura M A1 - Antoniou, Antonis C A1 - Barbieri, Caterina A1 - Coviello, Andrea D A1 - Cucca, Francesco A1 - Demerath, Ellen W A1 - Dunning, Alison M A1 - Gandin, Ilaria A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Huang, Jinyan A1 - Jackson, Rebecca D A1 - Karasik, David A1 - Kriebel, Jennifer A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langenberg, Claudia A1 - Li, Xin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Porteous, David A1 - Reiner, Alex P A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Scott, Robert A A1 - Stöckl, Doris A1 - Visser, Jenny A A1 - Völker, Uwe A1 - Vozzi, Diego A1 - Wilson, James G A1 - Zygmunt, Marek A1 - Boerwinkle, Eric A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Hayward, Caroline A1 - Hu, Frank B A1 - Liu, Simin A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Strauch, Konstantin A1 - Streeten, Elizabeth A A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Wellons, Melissa A1 - Franceschini, Nora A1 - Chasman, Daniel I A1 - Thorsteinsdottir, Unnur A1 - Murray, Anna A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Perry, John R B AB -

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26239645?dopt=Abstract ER - TY - JOUR T1 - Relevance of random biopsy at the transformation zone when colposcopy is negative. JF - Obstet Gynecol Y1 - 2015 A1 - Wiesenfeld, Uri A1 - Mangino, Francesco Paolo A1 - Toffoletti, Franco Giovanni A1 - Ricci, Giuseppe KW - Cervical Intraepithelial Neoplasia KW - Colposcopy KW - Early Detection of Cancer KW - Female KW - Humans KW - Papillomavirus Infections KW - Precancerous Conditions KW - Uterine Cervical Neoplasms VL - 125 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25611629?dopt=Abstract ER - TY - JOUR T1 - Association analysis of bitter receptor genes in five isolated populations identifies a significant correlation between TAS2R43 variants and coffee liking. JF - PLoS One Y1 - 2014 A1 - Pirastu, Nicola A1 - Kooyman, Maarten A1 - Traglia, Michela A1 - Robino, Antonietta A1 - Willems, Sara M A1 - Pistis, Giorgio A1 - d'Adamo, Pio A1 - Amin, Najaf A1 - D'Eustacchio, Angela A1 - Navarini, Luciano A1 - Sala, Cinzia A1 - Karssen, Lennart C A1 - van Duijn, Cornelia A1 - Toniolo, Daniela A1 - Gasparini, Paolo KW - Coffee KW - Genetic Association Studies KW - Humans KW - Polymorphism, Single Nucleotide KW - Receptors, G-Protein-Coupled KW - Taste AB -

Coffee, one of the most popular beverages in the world, contains many different physiologically active compounds with a potential impact on people's health. Despite the recent attention given to the genetic basis of its consumption, very little has been done in understanding genes influencing coffee preference among different individuals. Given its markedly bitter taste, we decided to verify if bitter receptor genes (TAS2Rs) variants affect coffee liking. In this light, 4066 people from different parts of Europe and Central Asia filled in a field questionnaire on coffee liking. They have been consequently recruited and included in the study. Eighty-eight SNPs covering the 25 TAS2R genes were selected from the available imputed ones and used to run association analysis for coffee liking. A significant association was detected with three SNP: one synonymous and two functional variants (W35S and H212R) on the TAS2R43 gene. Both variants have been shown to greatly reduce in vitro protein activity. Surprisingly the wild type allele, which corresponds to the functional form of the protein, is associated to higher liking of coffee. Since the hTAS2R43 receptor is sensible to caffeine, we verified if the detected variants produced differences in caffeine bitter perception on a subsample of people coming from the FVG cohort. We found a significant association between differences in caffeine perception and the H212R variant but not with the W35S, which suggests that the effect of the TAS2R43 gene on coffee liking is mediated by caffeine and in particular by the H212R variant. No other significant association was found with other TAS2R genes. In conclusion, the present study opens new perspectives in the understanding of coffee liking. Further studies are needed to clarify the role of the TAS2R43 gene in coffee hedonics and to identify which other genes and pathways are involved in its genetics.

VL - 9 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24647340?dopt=Abstract ER - TY - JOUR T1 - Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis. JF - J Am Soc Nephrol Y1 - 2014 A1 - Olden, Matthias A1 - Corre, Tanguy A1 - Hayward, Caroline A1 - Toniolo, Daniela A1 - Ulivi, Sheila A1 - Gasparini, Paolo A1 - Pistis, Giorgio A1 - Hwang, Shih-Jen A1 - Bergmann, Sven A1 - Campbell, Harry A1 - Cocca, Massimiliano A1 - Gandin, Ilaria A1 - Girotto, Giorgia A1 - Glaudemans, Bob A1 - Hastie, Nicholas D A1 - Loffing, Johannes A1 - Polasek, Ozren A1 - Rampoldi, Luca A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Traglia, Michela A1 - Vollenweider, Peter A1 - Vuckovic, Dragana A1 - Youhanna, Sonia A1 - Weber, Julien A1 - Wright, Alan F A1 - Kutalik, Zoltán A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Devuyst, Olivier KW - Creatinine KW - European Continental Ancestry Group KW - Genetic Variation KW - Humans KW - Polymorphism, Single Nucleotide KW - Uromodulin AB -

Uromodulin is expressed exclusively in the thick ascending limb and is the most abundant protein excreted in normal urine. Variants in UMOD, which encodes uromodulin, are associated with renal function, and urinary uromodulin levels may be a biomarker for kidney disease. However, the genetic factors regulating uromodulin excretion are unknown. We conducted a meta-analysis of urinary uromodulin levels to identify associated common genetic variants in the general population. We included 10,884 individuals of European descent from three genetic isolates and three urban cohorts. Each study measured uromodulin indexed to creatinine and conducted linear regression analysis of approximately 2.5 million single nucleotide polymorphisms using an additive model. We also tested whether variants in genes expressed in the thick ascending limb associate with uromodulin levels. rs12917707, located near UMOD and previously associated with renal function and CKD, had the strongest association with urinary uromodulin levels (P<0.001). In all cohorts, carriers of a G allele of this variant had higher uromodulin levels than noncarriers did (geometric means 10.24, 14.05, and 17.67 μg/g creatinine for zero, one, or two copies of the G allele). rs12446492 in the adjacent gene PDILT (protein disulfide isomerase-like, testis expressed) also reached genome-wide significance (P<0.001). Regarding genes expressed in the thick ascending limb, variants in KCNJ1, SORL1, and CAB39 associated with urinary uromodulin levels. These data indicate that common variants in the UMOD promoter region may influence urinary uromodulin levels. They also provide insights into uromodulin biology and the association of UMOD variants with renal function.

VL - 25 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24578125?dopt=Abstract ER - TY - JOUR T1 - DNA mismatch repair gene MSH6 implicated in determining age at natural menopause. JF - Hum Mol Genet Y1 - 2014 A1 - Perry, John R B A1 - Hsu, Yi-Hsiang A1 - Chasman, Daniel I A1 - Johnson, Andrew D A1 - Elks, Cathy A1 - Albrecht, Eva A1 - Andrulis, Irene L A1 - Beesley, Jonathan A1 - Berenson, Gerald S A1 - Bergmann, Sven A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Brown, Judith A1 - Buring, Julie E A1 - Campbell, Harry A1 - Chang-Claude, Jenny A1 - Chenevix-Trench, Georgia A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cox, Angela A1 - Czene, Kamila A1 - d'Adamo, Adamo Pio A1 - Davies, Gail A1 - Deary, Ian J A1 - Dennis, Joe A1 - Easton, Douglas F A1 - Engelhardt, Ellen G A1 - Eriksson, Johan G A1 - Esko, Tõnu A1 - Fasching, Peter A A1 - Figueroa, Jonine D A1 - Flyger, Henrik A1 - Fraser, Abigail A1 - Garcia-Closas, Montse A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Giles, Graham A1 - Guenel, Pascal A1 - Hägg, Sara A1 - Hall, Per A1 - Hayward, Caroline A1 - Hopper, John A1 - Ingelsson, Erik A1 - Kardia, Sharon L R A1 - Kasiman, Katherine A1 - Knight, Julia A A1 - Lahti, Jari A1 - Lawlor, Debbie A A1 - Magnusson, Patrik K E A1 - Margolin, Sara A1 - Marsh, Julie A A1 - Metspalu, Andres A1 - Olson, Janet E A1 - Pennell, Craig E A1 - Polasek, Ozren A1 - Rahman, Iffat A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Rudan, Igor A1 - Rudolph, Anja A1 - Salumets, Andres A1 - Schmidt, Marjanka K A1 - Schoemaker, Minouk J A1 - Smith, Erin N A1 - Smith, Jennifer A A1 - Southey, Melissa A1 - Stöckl, Doris A1 - Swerdlow, Anthony J A1 - Thompson, Deborah J A1 - Truong, Therese A1 - Ulivi, Sheila A1 - Waldenberger, Melanie A1 - Wang, Qin A1 - Wild, Sarah A1 - Wilson, James F A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Ong, Ken K A1 - Murabito, Joanne M A1 - Karasik, David A1 - Murray, Anna KW - Age Factors KW - DNA-Binding Proteins KW - Female KW - Genome-Wide Association Study KW - Humans KW - Menopause KW - Polymorphism, Single Nucleotide AB -

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.

VL - 23 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24357391?dopt=Abstract ER - TY - JOUR T1 - A general approach for haplotype phasing across the full spectrum of relatedness. JF - PLoS Genet Y1 - 2014 A1 - O'Connell, Jared A1 - Gurdasani, Deepti A1 - Delaneau, Olivier A1 - Pirastu, Nicola A1 - Ulivi, Sheila A1 - Cocca, Massimiliano A1 - Traglia, Michela A1 - Huang, Jie A1 - Huffman, Jennifer E A1 - Rudan, Igor A1 - McQuillan, Ruth A1 - Fraser, Ross M A1 - Campbell, Harry A1 - Polasek, Ozren A1 - Asiki, Gershim A1 - Ekoru, Kenneth A1 - Hayward, Caroline A1 - Wright, Alan F A1 - Vitart, Veronique A1 - Navarro, Pau A1 - Zagury, Jean-Francois A1 - Wilson, James F A1 - Toniolo, Daniela A1 - Gasparini, Paolo A1 - Soranzo, Nicole A1 - Sandhu, Manjinder S A1 - Marchini, Jonathan KW - Chromosome Mapping KW - Cohort Effect KW - Family KW - Genotype KW - Haplotypes KW - Humans KW - Models, Genetic KW - Pedigree KW - Phenotype KW - Recombination, Genetic AB -

Many existing cohorts contain a range of relatedness between genotyped individuals, either by design or by chance. Haplotype estimation in such cohorts is a central step in many downstream analyses. Using genotypes from six cohorts from isolated populations and two cohorts from non-isolated populations, we have investigated the performance of different phasing methods designed for nominally 'unrelated' individuals. We find that SHAPEIT2 produces much lower switch error rates in all cohorts compared to other methods, including those designed specifically for isolated populations. In particular, when large amounts of IBD sharing is present, SHAPEIT2 infers close to perfect haplotypes. Based on these results we have developed a general strategy for phasing cohorts with any level of implicit or explicit relatedness between individuals. First SHAPEIT2 is run ignoring all explicit family information. We then apply a novel HMM method (duoHMM) to combine the SHAPEIT2 haplotypes with any family information to infer the inheritance pattern of each meiosis at all sites across each chromosome. This allows the correction of switch errors, detection of recombination events and genotyping errors. We show that the method detects numbers of recombination events that align very well with expectations based on genetic maps, and that it infers far fewer spurious recombination events than Merlin. The method can also detect genotyping errors and infer recombination events in otherwise uninformative families, such as trios and duos. The detected recombination events can be used in association scans for recombination phenotypes. The method provides a simple and unified approach to haplotype estimation, that will be of interest to researchers in the fields of human, animal and plant genetics.

VL - 10 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24743097?dopt=Abstract ER - TY - JOUR T1 - Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. JF - Nat Genet Y1 - 2014 A1 - Arking, Dan E A1 - Pulit, Sara L A1 - Crotti, Lia A1 - van der Harst, Pim A1 - Munroe, Patricia B A1 - Koopmann, Tamara T A1 - Sotoodehnia, Nona A1 - Rossin, Elizabeth J A1 - Morley, Michael A1 - Wang, Xinchen A1 - Johnson, Andrew D A1 - Lundby, Alicia A1 - Gudbjartsson, Daniel F A1 - Noseworthy, Peter A A1 - Eijgelsheim, Mark A1 - Bradford, Yuki A1 - Tarasov, Kirill V A1 - Dörr, Marcus A1 - Müller-Nurasyid, Martina A1 - Lahtinen, Annukka M A1 - Nolte, Ilja M A1 - Smith, Albert Vernon A1 - Bis, Joshua C A1 - Isaacs, Aaron A1 - Newhouse, Stephen J A1 - Evans, Daniel S A1 - Post, Wendy S A1 - Waggott, Daryl A1 - Lyytikäinen, Leo-Pekka A1 - Hicks, Andrew A A1 - Eisele, Lewin A1 - Ellinghaus, David A1 - Hayward, Caroline A1 - Navarro, Pau A1 - Ulivi, Sheila A1 - Tanaka, Toshiko A1 - Tester, David J A1 - Chatel, Stéphanie A1 - Gustafsson, Stefan A1 - Kumari, Meena A1 - Morris, Richard W A1 - Naluai, Åsa T A1 - Padmanabhan, Sandosh A1 - Kluttig, Alexander A1 - Strohmer, Bernhard A1 - Panayiotou, Andrie G A1 - Torres, Maria A1 - Knoflach, Michael A1 - Hubacek, Jaroslav A A1 - Slowikowski, Kamil A1 - Raychaudhuri, Soumya A1 - Kumar, Runjun D A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shuldiner, Alan R A1 - Alonso, Alvaro A1 - Bader, Joel S A1 - Ehret, Georg A1 - Huang, Hailiang A1 - Kao, W H Linda A1 - Strait, James B A1 - Macfarlane, Peter W A1 - Brown, Morris A1 - Caulfield, Mark J A1 - Samani, Nilesh J A1 - Kronenberg, Florian A1 - Willeit, Johann A1 - Smith, J Gustav A1 - Greiser, Karin H A1 - Meyer Zu Schwabedissen, Henriette A1 - Werdan, Karl A1 - Carella, Massimo A1 - Zelante, Leopoldo A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Wright, Alan F A1 - Griffin, Maura A1 - Daly, Mark J A1 - Arnar, David O A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Denny, Joshua C A1 - Roden, Dan M A1 - Zuvich, Rebecca L A1 - Emilsson, Valur A1 - Plump, Andrew S A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Yin, Xiaoyan A1 - Bobbo, Marco A1 - d'Adamo, Adamo P A1 - Iorio, Annamaria A1 - Sinagra, Gianfranco A1 - Carracedo, Angel A1 - Cummings, Steven R A1 - Nalls, Michael A A1 - Jula, Antti A1 - Kontula, Kimmo K A1 - Marjamaa, Annukka A1 - Oikarinen, Lasse A1 - Perola, Markus A1 - Porthan, Kimmo A1 - Erbel, Raimund A1 - Hoffmann, Per A1 - Jöckel, Karl-Heinz A1 - Kälsch, Hagen A1 - Nöthen, Markus M A1 - den Hoed, Marcel A1 - Loos, Ruth J F A1 - Thelle, Dag S A1 - Gieger, Christian A1 - Meitinger, Thomas A1 - Perz, Siegfried A1 - Peters, Annette A1 - Prucha, Hanna A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - de Boer, Rudolf A A1 - Franke, Lude A1 - van der Vleuten, Pieter A A1 - Beckmann, Britt Maria A1 - Martens, Eimo A1 - Bardai, Abdennasser A1 - Hofman, Nynke A1 - Wilde, Arthur A M A1 - Behr, Elijah R A1 - Dalageorgou, Chrysoula A1 - Giudicessi, John R A1 - Medeiros-Domingo, Argelia A1 - Barc, Julien A1 - Kyndt, Florence A1 - Probst, Vincent A1 - Ghidoni, Alice A1 - Insolia, Roberto A1 - Hamilton, Robert M A1 - Scherer, Stephen W A1 - Brandimarto, Jeffrey A1 - Margulies, Kenneth A1 - Moravec, Christine E A1 - del Greco M, Fabiola A1 - Fuchsberger, Christian A1 - O'Connell, Jeffrey R A1 - Lee, Wai K A1 - Watt, Graham C M A1 - Campbell, Harry A1 - Wild, Sarah H A1 - El Mokhtari, Nour E A1 - Frey, Norbert A1 - Asselbergs, Folkert W A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van den Berg, Maarten P A1 - van Veldhuisen, Dirk J A1 - Kellis, Manolis A1 - Krijthe, Bouwe P A1 - Franco, Oscar H A1 - Hofman, Albert A1 - Kors, Jan A A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Kedenko, Lyudmyla A1 - Lamina, Claudia A1 - Oostra, Ben A A1 - Abecasis, Goncalo R A1 - Lakatta, Edward G A1 - Mulas, Antonella A1 - Orru, Marco A1 - Schlessinger, David A1 - Uda, Manuela A1 - Markus, Marcello R P A1 - Völker, Uwe A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Arnlöv, Johan A1 - Lind, Lars A1 - Sundström, Johan A1 - Syvänen, Ann-Christine A1 - Kivimaki, Mika A1 - Kähönen, Mika A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Viikari, Jorma S A1 - Adamkova, Vera A1 - Kiechl, Stefan A1 - Brion, Maria A1 - Nicolaides, Andrew N A1 - Paulweber, Bernhard A1 - Haerting, Johannes A1 - Dominiczak, Anna F A1 - Nyberg, Fredrik A1 - Whincup, Peter H A1 - Hingorani, Aroon D A1 - Schott, Jean-Jacques A1 - Bezzina, Connie R A1 - Ingelsson, Erik A1 - Ferrucci, Luigi A1 - Gasparini, Paolo A1 - Wilson, James F A1 - Rudan, Igor A1 - Franke, Andre A1 - Mühleisen, Thomas W A1 - Pramstaller, Peter P A1 - Lehtimäki, Terho J A1 - Paterson, Andrew D A1 - Parsa, Afshin A1 - Liu, Yongmei A1 - van Duijn, Cornelia M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Jamshidi, Yalda A1 - Salomaa, Veikko A1 - Felix, Stephan B A1 - Sanna, Serena A1 - Ritchie, Marylyn D A1 - Stricker, Bruno H A1 - Stefansson, Kari A1 - Boyer, Laurie A A1 - Cappola, Thomas P A1 - Olsen, Jesper V A1 - Lage, Kasper A1 - Schwartz, Peter J A1 - Kääb, Stefan A1 - Chakravarti, Aravinda A1 - Ackerman, Michael J A1 - Pfeufer, Arne A1 - de Bakker, Paul I W A1 - Newton-Cheh, Christopher KW - Adult KW - Aged KW - Arrhythmias, Cardiac KW - Calcium Signaling KW - Death, Sudden, Cardiac KW - Electrocardiography KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Ventricles KW - Humans KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Myocardium KW - Polymorphism, Single Nucleotide AB -

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24952745?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of sexual maturation in males and females highlights a role for body mass and menarche loci in male puberty. JF - Hum Mol Genet Y1 - 2014 A1 - Cousminer, Diana L A1 - Stergiakouli, Evangelia A1 - Berry, Diane J A1 - Ang, Wei A1 - Groen-Blokhuis, Maria M A1 - Körner, Antje A1 - Siitonen, Niina A1 - Ntalla, Ioanna A1 - Marinelli, Marcella A1 - Perry, John R B A1 - Kettunen, Johannes A1 - Jansen, Rick A1 - Surakka, Ida A1 - Timpson, Nicholas J A1 - Ring, Susan A1 - McMahon, George A1 - Power, Chris A1 - Wang, Carol A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Lehtimäki, Terho A1 - Middeldorp, Christel M A1 - Hulshoff Pol, Hilleke E A1 - Neef, Madlen A1 - Weise, Sebastian A1 - Pahkala, Katja A1 - Niinikoski, Harri A1 - Zeggini, Eleftheria A1 - Panoutsopoulou, Kalliope A1 - Bustamante, Mariona A1 - Penninx, Brenda W J H A1 - Murabito, Joanne A1 - Torrent, Maties A1 - Dedoussis, George V A1 - Kiess, Wieland A1 - Boomsma, Dorret I A1 - Pennell, Craig E A1 - Raitakari, Olli T A1 - Hyppönen, Elina A1 - Davey Smith, George A1 - Ripatti, Samuli A1 - McCarthy, Mark I A1 - Widen, Elisabeth AB -

Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11 000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of myocardin-like 2 (MKL2) (P = 8.9 × 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P = 4.6 × 10(-5)) and short adult stature (p = 7.5 × 10(-6)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes. Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, body mass index (BMI)-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.

VL - 23 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24770850?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2014 A1 - Murray, Christopher J L A1 - Ortblad, Katrina F A1 - Guinovart, Caterina A1 - Lim, Stephen S A1 - Wolock, Timothy M A1 - Roberts, D Allen A1 - Dansereau, Emily A A1 - Graetz, Nicholas A1 - Barber, Ryan M A1 - Brown, Jonathan C A1 - Wang, Haidong A1 - Duber, Herbert C A1 - Naghavi, Mohsen A1 - Dicker, Daniel A1 - Dandona, Lalit A1 - Salomon, Joshua A A1 - Heuton, Kyle R A1 - Foreman, Kyle A1 - Phillips, David E A1 - Fleming, Thomas D A1 - Flaxman, Abraham D A1 - Phillips, Bryan K A1 - Johnson, Elizabeth K A1 - Coggeshall, Megan S A1 - Abd-Allah, Foad A1 - Abera, Semaw Ferede A1 - Abraham, Jerry P A1 - Abubakar, Ibrahim A1 - Abu-Raddad, Laith J A1 - Abu-Rmeileh, Niveen Me A1 - Achoki, Tom A1 - Adeyemo, Austine Olufemi A1 - Adou, Arsène Kouablan A1 - Adsuar, José C A1 - Agardh, Emilie Elisabet A1 - Akena, Dickens A1 - Al Kahbouri, Mazin J A1 - Alasfoor, Deena A1 - Albittar, Mohammed I A1 - Alcalá-Cerra, Gabriel A1 - Alegretti, Miguel Angel A1 - Alemu, Zewdie Aderaw A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Alla, François A1 - Allen, Peter J A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Amini, Hassan A1 - Ammar, Walid A1 - Anderson, Benjamin O A1 - Antonio, Carl Abelardo T A1 - Anwari, Palwasha A1 - Arnlöv, Johan A1 - Arsenijevic, Valentina S Arsic A1 - Artaman, Ali A1 - Asghar, Rana J A1 - Assadi, Reza A1 - Atkins, Lydia S A1 - Badawi, Alaa A1 - Balakrishnan, Kalpana A1 - Banerjee, Amitava A1 - Basu, Sanjay A1 - Beardsley, Justin A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Bernabe, Eduardo A1 - Beyene, Tariku Jibat A1 - Bhala, Neeraj A1 - Bhalla, Ashish A1 - Bhutta, Zulfiqar A A1 - Abdulhak, Aref Bin A1 - Binagwaho, Agnes A1 - Blore, Jed D A1 - Basara, Berrak Bora A1 - Bose, Dipan A1 - Brainin, Michael A1 - Breitborde, Nicholas A1 - Castañeda-Orjuela, Carlos A A1 - Catalá-López, Ferrán A1 - Chadha, Vineet K A1 - Chang, Jung-Chen A1 - Chiang, Peggy Pei-Chia A1 - Chuang, Ting-Wu A1 - Colomar, Mercedes A1 - Cooper, Leslie Trumbull A1 - Cooper, Cyrus A1 - Courville, Karen J A1 - Cowie, Benjamin C A1 - Criqui, Michael H A1 - Dandona, Rakhi A1 - Dayama, Anand A1 - De Leo, Diego A1 - Degenhardt, Louisa A1 - del Pozo-Cruz, Borja A1 - Deribe, Kebede A1 - Des Jarlais, Don C A1 - Dessalegn, Muluken A1 - Dharmaratne, Samath D A1 - Dilmen, Uğur A1 - Ding, Eric L A1 - Driscoll, Tim R A1 - Durrani, Adnan M A1 - Ellenbogen, Richard G A1 - Ermakov, Sergey Petrovich A1 - Esteghamati, Alireza A1 - Faraon, Emerito Jose A A1 - Farzadfar, Farshad A1 - Fereshtehnejad, Seyed-Mohammad A1 - Fijabi, Daniel Obadare A1 - Forouzanfar, Mohammad H A1 - Fra Paleo, Urbano A1 - Gaffikin, Lynne A1 - Gamkrelidze, Amiran A1 - Gankpé, Fortuné Gbètoho A1 - Geleijnse, Johanna M A1 - Gessner, Bradford D A1 - Gibney, Katherine B A1 - Ginawi, Ibrahim Abdelmageem Mohamed A1 - Glaser, Elizabeth L A1 - Gona, Philimon A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Gugnani, Harish Chander A1 - Gupta, Rajeev A1 - Gupta, Rahul A1 - Hafezi-Nejad, Nima A1 - Hamadeh, Randah Ribhi A1 - Hammami, Mouhanad A1 - Hankey, Graeme J A1 - Harb, Hilda L A1 - Haro, Josep Maria A1 - Havmoeller, Rasmus A1 - Hay, Simon I A1 - Hedayati, Mohammad T A1 - Pi, Ileana B Heredia A1 - Hoek, Hans W A1 - Hornberger, John C A1 - Hosgood, H Dean A1 - Hotez, Peter J A1 - Hoy, Damian G A1 - Huang, John J A1 - Iburg, Kim M A1 - Idrisov, Bulat T A1 - Innos, Kaire A1 - Jacobsen, Kathryn H A1 - Jeemon, Panniyammakal A1 - Jensen, Paul N A1 - Jha, Vivekanand A1 - Jiang, Guohong A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kan, Haidong A1 - Kankindi, Ida A1 - Karam, Nadim E A1 - Karch, André A1 - Karema, Corine Kakizi A1 - Kaul, Anil A1 - Kawakami, Norito A1 - Kazi, Dhruv S A1 - Kemp, Andrew H A1 - Kengne, Andre Pascal A1 - Keren, Andre A1 - Kereselidze, Maia A1 - Khader, Yousef Saleh A1 - Khalifa, Shams Eldin Ali Hassan A1 - Khan, Ejaz Ahmed A1 - Khang, Young-Ho A1 - Khonelidze, Irma A1 - Kinfu, Yohannes A1 - Kinge, Jonas M A1 - Knibbs, Luke A1 - Kokubo, Yoshihiro A1 - Kosen, S A1 - Defo, Barthelemy Kuate A1 - Kulkarni, Veena S A1 - Kulkarni, Chanda A1 - Kumar, Kaushalendra A1 - Kumar, Ravi B A1 - Kumar, G Anil A1 - Kwan, Gene F A1 - Lai, Taavi A1 - Balaji, Arjun Lakshmana A1 - Lam, Hilton A1 - Lan, Qing A1 - Lansingh, Van C A1 - Larson, Heidi J A1 - Larsson, Anders A1 - Lee, Jong-Tae A1 - Leigh, James A1 - Leinsalu, Mall A1 - Leung, Ricky A1 - Li, Yichong A1 - Li, Yongmei A1 - de Lima, Graça Maria Ferreira A1 - Lin, Hsien-Ho A1 - Lipshultz, Steven E A1 - Liu, Shiwei A1 - Liu, Yang A1 - Lloyd, Belinda K A1 - Lotufo, Paulo A A1 - Machado, Vasco Manuel Pedro A1 - Maclachlan, Jennifer H A1 - Magis-Rodriguez, Carlos A1 - Majdan, Marek A1 - Mapoma, Christopher Chabila A1 - Marcenes, Wagner A1 - Marzan, Melvin Barrientos A1 - Masci, Joseph R A1 - Mashal, Mohammad Taufiq A1 - Mason-Jones, Amanda J A1 - Mayosi, Bongani M A1 - Mazorodze, Tasara T A1 - Mckay, Abigail Cecilia A1 - Meaney, Peter A A1 - Mehndiratta, Man Mohan A1 - Mejia-Rodriguez, Fabiola A1 - Melaku, Yohannes Adama A1 - Memish, Ziad A A1 - Mendoza, Walter A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mohammad, Karzan Abdulmuhsin A1 - Mokdad, Ali H A1 - Mola, Glen Liddell A1 - Monasta, Lorenzo A1 - Montico, Marcella A1 - Moore, Ami R A1 - Mori, Rintaro A1 - Moturi, Wilkister Nyaora A1 - Mukaigawara, Mitsuru A1 - Murthy, Kinnari S A1 - Naheed, Aliya A1 - Naidoo, Kovin S A1 - Naldi, Luigi A1 - Nangia, Vinay A1 - Narayan, K M Venkat A1 - Nash, Denis A1 - Nejjari, Chakib A1 - Nelson, Robert G A1 - Neupane, Sudan Prasad A1 - Newton, Charles R A1 - Ng, Marie A1 - Nisar, Muhammad Imran A1 - Nolte, Sandra A1 - Norheim, Ole F A1 - Nowaseb, Vincent A1 - Nyakarahuka, Luke A1 - Oh, In-Hwan A1 - Ohkubo, Takayoshi A1 - Olusanya, Bolajoko O A1 - Omer, Saad B A1 - Opio, John Nelson A1 - Orisakwe, Orish Ebere A1 - Pandian, Jeyaraj D A1 - Papachristou, Christina A1 - Caicedo, Angel J Paternina A1 - Patten, Scott B A1 - Paul, Vinod K A1 - Pavlin, Boris Igor A1 - Pearce, Neil A1 - Pereira, David M A1 - Pervaiz, Aslam A1 - Pesudovs, Konrad A1 - Petzold, Max A1 - Pourmalek, Farshad A1 - Qato, Dima A1 - Quezada, Amado D A1 - Quistberg, D Alex A1 - Rafay, Anwar A1 - Rahimi, Kazem A1 - Rahimi-Movaghar, Vafa A1 - ur Rahman, Sajjad A1 - Raju, Murugesan A1 - Rana, Saleem M A1 - Razavi, Homie A1 - Reilly, Robert Quentin A1 - Remuzzi, Giuseppe A1 - Richardus, Jan Hendrik A1 - Ronfani, Luca A1 - Roy, Nobhojit A1 - Sabin, Nsanzimana A1 - Saeedi, Mohammad Yahya A1 - Sahraian, Mohammad Ali A1 - Samonte, Genesis May J A1 - Sawhney, Monika A1 - Schneider, Ione J C A1 - Schwebel, David C A1 - Seedat, Soraya A1 - Sepanlou, Sadaf G A1 - Servan-Mori, Edson E A1 - Sheikhbahaei, Sara A1 - Shibuya, Kenji A1 - Shin, Hwashin Hyun A1 - Shiue, Ivy A1 - Shivakoti, Rupak A1 - Sigfusdottir, Inga Dora A1 - Silberberg, Donald H A1 - Silva, Andrea P A1 - Simard, Edgar P A1 - Singh, Jasvinder A A1 - Skirbekk, Vegard A1 - Sliwa, Karen A1 - Soneji, Samir A1 - Soshnikov, Sergey S A1 - Sreeramareddy, Chandrashekhar T A1 - Stathopoulou, Vasiliki Kalliopi A1 - Stroumpoulis, Konstantinos A1 - Swaminathan, Soumya A1 - Sykes, Bryan L A1 - Tabb, Karen M A1 - Talongwa, Roberto Tchio A1 - Tenkorang, Eric Yeboah A1 - Terkawi, Abdullah Sulieman A1 - Thomson, Alan J A1 - Thorne-Lyman, Andrew L A1 - Towbin, Jeffrey A A1 - Traebert, Jefferson A1 - Tran, Bach X A1 - Dimbuene, Zacharie Tsala A1 - Tsilimbaris, Miltiadis A1 - Uchendu, Uche S A1 - Ukwaja, Kingsley N A1 - Uzun, Selen Begüm A1 - Vallely, Andrew J A1 - Vasankari, Tommi J A1 - Venketasubramanian, N A1 - Violante, Francesco S A1 - Vlassov, Vasiliy Victorovich A1 - Vollset, Stein Emil A1 - Waller, Stephen A1 - Wallin, Mitchell T A1 - Wang, Linhong A1 - Wang, XiaoRong A1 - Wang, Yanping A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Westerman, Ronny A1 - White, Richard A A1 - Wilkinson, James D A1 - Williams, Thomas Neil A1 - Woldeyohannes, Solomon Meseret A1 - Wong, John Q A1 - Xu, Gelin A1 - Yang, Yang C A1 - Yano, Yuichiro A1 - Yentur, Gokalp Kadri A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa A1 - Yu, Chuanhua A1 - Jin, Kim Yun A1 - El Sayed Zaki, Maysaa A1 - Zhao, Yong A1 - Zheng, Yingfeng A1 - Zhou, Maigeng A1 - Zhu, Jun A1 - Zou, Xiao Nong A1 - Lopez, Alan D A1 - Vos, Theo KW - Age Distribution KW - Epidemics KW - Female KW - Global Health KW - HIV Infections KW - Humans KW - Incidence KW - Malaria KW - Male KW - Mortality KW - Organizational Objectives KW - Sex Distribution KW - Tuberculosis AB -

BACKGROUND: The Millennium Declaration in 2000 brought special global attention to HIV, tuberculosis, and malaria through the formulation of Millennium Development Goal (MDG) 6. The Global Burden of Disease 2013 study provides a consistent and comprehensive approach to disease estimation for between 1990 and 2013, and an opportunity to assess whether accelerated progress has occured since the Millennium Declaration.

METHODS: To estimate incidence and mortality for HIV, we used the UNAIDS Spectrum model appropriately modified based on a systematic review of available studies of mortality with and without antiretroviral therapy (ART). For concentrated epidemics, we calibrated Spectrum models to fit vital registration data corrected for misclassification of HIV deaths. In generalised epidemics, we minimised a loss function to select epidemic curves most consistent with prevalence data and demographic data for all-cause mortality. We analysed counterfactual scenarios for HIV to assess years of life saved through prevention of mother-to-child transmission (PMTCT) and ART. For tuberculosis, we analysed vital registration and verbal autopsy data to estimate mortality using cause of death ensemble modelling. We analysed data for corrected case-notifications, expert opinions on the case-detection rate, prevalence surveys, and estimated cause-specific mortality using Bayesian meta-regression to generate consistent trends in all parameters. We analysed malaria mortality and incidence using an updated cause of death database, a systematic analysis of verbal autopsy validation studies for malaria, and recent studies (2010-13) of incidence, drug resistance, and coverage of insecticide-treated bednets.

FINDINGS: Globally in 2013, there were 1·8 million new HIV infections (95% uncertainty interval 1·7 million to 2·1 million), 29·2 million prevalent HIV cases (28·1 to 31·7), and 1·3 million HIV deaths (1·3 to 1·5). At the peak of the epidemic in 2005, HIV caused 1·7 million deaths (1·6 million to 1·9 million). Concentrated epidemics in Latin America and eastern Europe are substantially smaller than previously estimated. Through interventions including PMTCT and ART, 19·1 million life-years (16·6 million to 21·5 million) have been saved, 70·3% (65·4 to 76·1) in developing countries. From 2000 to 2011, the ratio of development assistance for health for HIV to years of life saved through intervention was US$4498 in developing countries. Including in HIV-positive individuals, all-form tuberculosis incidence was 7·5 million (7·4 million to 7·7 million), prevalence was 11·9 million (11·6 million to 12·2 million), and number of deaths was 1·4 million (1·3 million to 1·5 million) in 2013. In the same year and in only individuals who were HIV-negative, all-form tuberculosis incidence was 7·1 million (6·9 million to 7·3 million), prevalence was 11·2 million (10·8 million to 11·6 million), and number of deaths was 1·3 million (1·2 million to 1·4 million). Annualised rates of change (ARC) for incidence, prevalence, and death became negative after 2000. Tuberculosis in HIV-negative individuals disproportionately occurs in men and boys (versus women and girls); 64·0% of cases (63·6 to 64·3) and 64·7% of deaths (60·8 to 70·3). Globally, malaria cases and deaths grew rapidly from 1990 reaching a peak of 232 million cases (143 million to 387 million) in 2003 and 1·2 million deaths (1·1 million to 1·4 million) in 2004. Since 2004, child deaths from malaria in sub-Saharan Africa have decreased by 31·5% (15·7 to 44·1). Outside of Africa, malaria mortality has been steadily decreasing since 1990.

INTERPRETATION: Our estimates of the number of people living with HIV are 18·7% smaller than UNAIDS's estimates in 2012. The number of people living with malaria is larger than estimated by WHO. The number of people living with HIV, tuberculosis, or malaria have all decreased since 2000. At the global level, upward trends for malaria and HIV deaths have been reversed and declines in tuberculosis deaths have accelerated. 101 countries (74 of which are developing) still have increasing HIV incidence. Substantial progress since the Millennium Declaration is an encouraging sign of the effect of global action.

FUNDING: Bill & Melinda Gates Foundation.

VL - 384 IS - 9947 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25059949?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national levels and causes of maternal mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2014 A1 - Kassebaum, Nicholas J A1 - Bertozzi-Villa, Amelia A1 - Coggeshall, Megan S A1 - Shackelford, Katya A A1 - Steiner, Caitlyn A1 - Heuton, Kyle R A1 - Gonzalez-Medina, Diego A1 - Barber, Ryan A1 - Huynh, Chantal A1 - Dicker, Daniel A1 - Templin, Tara A1 - Wolock, Timothy M A1 - Ozgoren, Ayse Abbasoglu A1 - Abd-Allah, Foad A1 - Abera, Semaw Ferede A1 - Abubakar, Ibrahim A1 - Achoki, Tom A1 - Adelekan, Ademola A1 - Ademi, Zanfina A1 - Adou, Arsène Kouablan A1 - Adsuar, José C A1 - Agardh, Emilie E A1 - Akena, Dickens A1 - Alasfoor, Deena A1 - Alemu, Zewdie Aderaw A1 - Alfonso-Cristancho, Rafael A1 - Alhabib, Samia A1 - Ali, Raghib A1 - Al Kahbouri, Mazin J A1 - Alla, François A1 - Allen, Peter J A1 - AlMazroa, Mohammad A A1 - Alsharif, Ubai A1 - Alvarez, Elena A1 - Alvis-Guzmán, Nelson A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Amini, Hassan A1 - Ammar, Walid A1 - Antonio, Carl A T A1 - Anwari, Palwasha A1 - Arnlöv, Johan A1 - Arsenijevic, Valentina S Arsic A1 - Artaman, Ali A1 - Asad, Majed Masoud A1 - Asghar, Rana J A1 - Assadi, Reza A1 - Atkins, Lydia S A1 - Badawi, Alaa A1 - Balakrishnan, Kalpana A1 - Basu, Arindam A1 - Basu, Sanjay A1 - Beardsley, Justin A1 - Bedi, Neeraj A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Bernabe, Eduardo A1 - Beyene, Tariku J A1 - Bhutta, Zulfiqar A1 - Bin Abdulhak, Aref A1 - Blore, Jed D A1 - Basara, Berrak Bora A1 - Bose, Dipan A1 - Breitborde, Nicholas A1 - Cárdenas, Rosario A1 - Castañeda-Orjuela, Carlos A A1 - Castro, Ruben Estanislao A1 - Catalá-López, Ferrán A1 - Cavlin, Alanur A1 - Chang, Jung-Chen A1 - Che, Xuan A1 - Christophi, Costas A A1 - Chugh, Sumeet S A1 - Cirillo, Massimo A1 - Colquhoun, Samantha M A1 - Cooper, Leslie Trumbull A1 - Cooper, Cyrus A1 - da Costa Leite, Iuri A1 - Dandona, Lalit A1 - Dandona, Rakhi A1 - Davis, Adrian A1 - Dayama, Anand A1 - Degenhardt, Louisa A1 - De Leo, Diego A1 - del Pozo-Cruz, Borja A1 - Deribe, Kebede A1 - Dessalegn, Muluken A1 - deVeber, Gabrielle A A1 - Dharmaratne, Samath D A1 - Dilmen, Uğur A1 - Ding, Eric L A1 - Dorrington, Rob E A1 - Driscoll, Tim R A1 - Ermakov, Sergei Petrovich A1 - Esteghamati, Alireza A1 - Faraon, Emerito Jose A A1 - Farzadfar, Farshad A1 - Felicio, Manuela Mendonca A1 - Fereshtehnejad, Seyed-Mohammad A1 - de Lima, Graça Maria Ferreira A1 - Forouzanfar, Mohammad H A1 - França, Elisabeth B A1 - Gaffikin, Lynne A1 - Gambashidze, Ketevan A1 - Gankpé, Fortuné Gbètoho A1 - Garcia, Ana C A1 - Geleijnse, Johanna M A1 - Gibney, Katherine B A1 - Giroud, Maurice A1 - Glaser, Elizabeth L A1 - Goginashvili, Ketevan A1 - Gona, Philimon A1 - González-Castell, Dinorah A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Gugnani, Harish Chander A1 - Gupta, Rahul A1 - Gupta, Rajeev A1 - Hafezi-Nejad, Nima A1 - Hamadeh, Randah Ribhi A1 - Hammami, Mouhanad A1 - Hankey, Graeme J A1 - Harb, Hilda L A1 - Havmoeller, Rasmus A1 - Hay, Simon I A1 - Pi, Ileana B Heredia A1 - Hoek, Hans W A1 - Hosgood, H Dean A1 - Hoy, Damian G A1 - Husseini, Abdullatif A1 - Idrisov, Bulat T A1 - Innos, Kaire A1 - Inoue, Manami A1 - Jacobsen, Kathryn H A1 - Jahangir, Eiman A1 - Jee, Sun Ha A1 - Jensen, Paul N A1 - Jha, Vivekanand A1 - Jiang, Guohong A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kabagambe, Edmond Kato A1 - Kan, Haidong A1 - Karam, Nadim E A1 - Karch, André A1 - Karema, Corine Kakizi A1 - Kaul, Anil A1 - Kawakami, Norito A1 - Kazanjan, Konstantin A1 - Kazi, Dhruv S A1 - Kemp, Andrew H A1 - Kengne, Andre Pascal A1 - Kereselidze, Maia A1 - Khader, Yousef Saleh A1 - Khalifa, Shams Eldin Ali Hassan A1 - Khan, Ejaz Ahmed A1 - Khang, Young-Ho A1 - Knibbs, Luke A1 - Kokubo, Yoshihiro A1 - Kosen, Soewarta A1 - Defo, Barthelemy Kuate A1 - Kulkarni, Chanda A1 - Kulkarni, Veena S A1 - Kumar, G Anil A1 - Kumar, Kaushalendra A1 - Kumar, Ravi B A1 - Kwan, Gene A1 - Lai, Taavi A1 - Lalloo, Ratilal A1 - Lam, Hilton A1 - Lansingh, Van C A1 - Larsson, Anders A1 - Lee, Jong-Tae A1 - Leigh, James A1 - Leinsalu, Mall A1 - Leung, Ricky A1 - Li, Xiaohong A1 - Li, Yichong A1 - Li, Yongmei A1 - Liang, Juan A1 - Liang, Xiaofeng A1 - Lim, Stephen S A1 - Lin, Hsien-Ho A1 - Lipshultz, Steven E A1 - Liu, Shiwei A1 - Liu, Yang A1 - Lloyd, Belinda K A1 - London, Stephanie J A1 - Lotufo, Paulo A A1 - Ma, Jixiang A1 - Ma, Stefan A1 - Machado, Vasco Manuel Pedro A1 - Mainoo, Nana Kwaku A1 - Majdan, Marek A1 - Mapoma, Christopher Chabila A1 - Marcenes, Wagner A1 - Marzan, Melvin Barrientos A1 - Mason-Jones, Amanda J A1 - Mehndiratta, Man Mohan A1 - Mejia-Rodriguez, Fabiola A1 - Memish, Ziad A A1 - Mendoza, Walter A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mokdad, Ali H A1 - Mola, Glen Liddell A1 - Monasta, Lorenzo A1 - de la Cruz Monis, Jonathan A1 - Hernandez, Julio Cesar Montañez A1 - Moore, Ami R A1 - Moradi-Lakeh, Maziar A1 - Mori, Rintaro A1 - Mueller, Ulrich O A1 - Mukaigawara, Mitsuru A1 - Naheed, Aliya A1 - Naidoo, Kovin S A1 - Nand, Devina A1 - Nangia, Vinay A1 - Nash, Denis A1 - Nejjari, Chakib A1 - Nelson, Robert G A1 - Neupane, Sudan Prasad A1 - Newton, Charles R A1 - Ng, Marie A1 - Nieuwenhuijsen, Mark J A1 - Nisar, Muhammad Imran A1 - Nolte, Sandra A1 - Norheim, Ole F A1 - Nyakarahuka, Luke A1 - Oh, In-Hwan A1 - Ohkubo, Takayoshi A1 - Olusanya, Bolajoko O A1 - Omer, Saad B A1 - Opio, John Nelson A1 - Orisakwe, Orish Ebere A1 - Pandian, Jeyaraj D A1 - Papachristou, Christina A1 - Park, Jae-Hyun A1 - Caicedo, Angel J Paternina A1 - Patten, Scott B A1 - Paul, Vinod K A1 - Pavlin, Boris Igor A1 - Pearce, Neil A1 - Pereira, David M A1 - Pesudovs, Konrad A1 - Petzold, Max A1 - Poenaru, Dan A1 - Polanczyk, Guilherme V A1 - Polinder, Suzanne A1 - Pope, Dan A1 - Pourmalek, Farshad A1 - Qato, Dima A1 - Quistberg, D Alex A1 - Rafay, Anwar A1 - Rahimi, Kazem A1 - Rahimi-Movaghar, Vafa A1 - ur Rahman, Sajjad A1 - Raju, Murugesan A1 - Rana, Saleem M A1 - Refaat, Amany A1 - Ronfani, Luca A1 - Roy, Nobhojit A1 - Pimienta, Tania Georgina Sánchez A1 - Sahraian, Mohammad Ali A1 - Salomon, Joshua A A1 - Sampson, Uchechukwu A1 - Santos, Itamar S A1 - Sawhney, Monika A1 - Sayinzoga, Felix A1 - Schneider, Ione J C A1 - Schumacher, Austin A1 - Schwebel, David C A1 - Seedat, Soraya A1 - Sepanlou, Sadaf G A1 - Servan-Mori, Edson E A1 - Shakh-Nazarova, Marina A1 - Sheikhbahaei, Sara A1 - Shibuya, Kenji A1 - Shin, Hwashin Hyun A1 - Shiue, Ivy A1 - Sigfusdottir, Inga Dora A1 - Silberberg, Donald H A1 - Silva, Andrea P A1 - Singh, Jasvinder A A1 - Skirbekk, Vegard A1 - Sliwa, Karen A1 - Soshnikov, Sergey S A1 - Sposato, Luciano A A1 - Sreeramareddy, Chandrashekhar T A1 - Stroumpoulis, Konstantinos A1 - Sturua, Lela A1 - Sykes, Bryan L A1 - Tabb, Karen M A1 - Talongwa, Roberto Tchio A1 - Tan, Feng A1 - Teixeira, Carolina Maria A1 - Tenkorang, Eric Yeboah A1 - Terkawi, Abdullah Sulieman A1 - Thorne-Lyman, Andrew L A1 - Tirschwell, David L A1 - Towbin, Jeffrey A A1 - Tran, Bach X A1 - Tsilimbaris, Miltiadis A1 - Uchendu, Uche S A1 - Ukwaja, Kingsley N A1 - Undurraga, Eduardo A A1 - Uzun, Selen Begüm A1 - Vallely, Andrew J A1 - van Gool, Coen H A1 - Vasankari, Tommi J A1 - Vavilala, Monica S A1 - Venketasubramanian, N A1 - Villalpando, Salvador A1 - Violante, Francesco S A1 - Vlassov, Vasiliy Victorovich A1 - Vos, Theo A1 - Waller, Stephen A1 - Wang, Haidong A1 - Wang, Linhong A1 - Wang, XiaoRong A1 - Wang, Yanping A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Westerman, Ronny A1 - Wilkinson, James D A1 - Woldeyohannes, Solomon Meseret A1 - Wong, John Q A1 - Wordofa, Muluemebet Abera A1 - Xu, Gelin A1 - Yang, Yang C A1 - Yano, Yuichiro A1 - Yentur, Gokalp Kadri A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Yoon, Seok-Jun A1 - Younis, Mustafa Z A1 - Yu, Chuanhua A1 - Jin, Kim Yun A1 - El Sayed Zaki, Maysaa A1 - Zhao, Yong A1 - Zheng, Yingfeng A1 - Zhou, Maigeng A1 - Zhu, Jun A1 - Zou, Xiao Nong A1 - Lopez, Alan D A1 - Naghavi, Mohsen A1 - Murray, Christopher J L A1 - Lozano, Rafael KW - Age Distribution KW - Cause of Death KW - Female KW - Global Health KW - HIV Infections KW - Humans KW - Maternal Mortality KW - Models, Statistical KW - Organizational Objectives KW - Pregnancy KW - Pregnancy Complications, Infectious KW - Risk Factors KW - Socioeconomic Factors KW - Time Factors AB -

BACKGROUND: The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100,000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.

METHODS: We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990-2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.

FINDINGS: 292,982 (95% UI 261,017-327,792) maternal deaths occurred in 2013, compared with 376,034 (343,483-407,574) in 1990. The global annual rate of change in the MMR was -0·3% (-1·1 to 0·6) from 1990 to 2003, and -2·7% (-3·9 to -1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290-2866) maternal deaths were related to HIV in 2013, 0·4% (0·2-0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1-1262·8) in South Sudan to 2·4 (1·6-3·6) in Iceland.

INTERPRETATION: Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.

FUNDING: Bill & Melinda Gates Foundation.

VL - 384 IS - 9947 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24797575?dopt=Abstract ER - TY - JOUR T1 - Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. JF - Lancet Y1 - 2014 A1 - Wang, Haidong A1 - Liddell, Chelsea A A1 - Coates, Matthew M A1 - Mooney, Meghan D A1 - Levitz, Carly E A1 - Schumacher, Austin E A1 - Apfel, Henry A1 - Iannarone, Marissa A1 - Phillips, Bryan A1 - Lofgren, Katherine T A1 - Sandar, Logan A1 - Dorrington, Rob E A1 - Rakovac, Ivo A1 - Jacobs, Troy A A1 - Liang, Xiaofeng A1 - Zhou, Maigeng A1 - Zhu, Jun A1 - Yang, Gonghuan A1 - Wang, Yanping A1 - Liu, Shiwei A1 - Li, Yichong A1 - Ozgoren, Ayse Abbasoglu A1 - Abera, Semaw Ferede A1 - Abubakar, Ibrahim A1 - Achoki, Tom A1 - Adelekan, Ademola A1 - Ademi, Zanfina A1 - Alemu, Zewdie Aderaw A1 - Allen, Peter J A1 - AlMazroa, Mohammad AbdulAziz A1 - Alvarez, Elena A1 - Amankwaa, Adansi A A1 - Amare, Azmeraw T A1 - Ammar, Walid A1 - Anwari, Palwasha A1 - Cunningham, Solveig Argeseanu A1 - Asad, Majed Masoud A1 - Assadi, Reza A1 - Banerjee, Amitava A1 - Basu, Sanjay A1 - Bedi, Neeraj A1 - Bekele, Tolesa A1 - Bell, Michelle L A1 - Bhutta, Zulfiqar A1 - Blore, Jed D A1 - Basara, Berrak Bora A1 - Boufous, Soufiane A1 - Breitborde, Nicholas A1 - Bruce, Nigel G A1 - Bui, Linh Ngoc A1 - Carapetis, Jonathan R A1 - Cárdenas, Rosario A1 - Carpenter, David O A1 - Caso, Valeria A1 - Castro, Ruben Estanislao A1 - Catalá-López, Ferrán A1 - Cavlin, Alanur A1 - Che, Xuan A1 - Chiang, Peggy Pei-Chia A1 - Chowdhury, Rajiv A1 - Christophi, Costas A A1 - Chuang, Ting-Wu A1 - Cirillo, Massimo A1 - da Costa Leite, Iuri A1 - Courville, Karen J A1 - Dandona, Lalit A1 - Dandona, Rakhi A1 - Davis, Adrian A1 - Dayama, Anand A1 - Deribe, Kebede A1 - Dharmaratne, Samath D A1 - Dherani, Mukesh K A1 - Dilmen, Uğur A1 - Ding, Eric L A1 - Edmond, Karen M A1 - Ermakov, Sergei Petrovich A1 - Farzadfar, Farshad A1 - Fereshtehnejad, Seyed-Mohammad A1 - Fijabi, Daniel Obadare A1 - Foigt, Nataliya A1 - Forouzanfar, Mohammad H A1 - Garcia, Ana C A1 - Geleijnse, Johanna M A1 - Gessner, Bradford D A1 - Goginashvili, Ketevan A1 - Gona, Philimon A1 - Goto, Atsushi A1 - Gouda, Hebe N A1 - Green, Mark A A1 - Greenwell, Karen Fern A1 - Gugnani, Harish Chander A1 - Gupta, Rahul A1 - Hamadeh, Randah Ribhi A1 - Hammami, Mouhanad A1 - Harb, Hilda L A1 - Hay, Simon A1 - Hedayati, Mohammad T A1 - Hosgood, H Dean A1 - Hoy, Damian G A1 - Idrisov, Bulat T A1 - Islami, Farhad A1 - Ismayilova, Samaya A1 - Jha, Vivekanand A1 - Jiang, Guohong A1 - Jonas, Jost B A1 - Juel, Knud A1 - Kabagambe, Edmond Kato A1 - Kazi, Dhruv S A1 - Kengne, Andre Pascal A1 - Kereselidze, Maia A1 - Khader, Yousef Saleh A1 - Khalifa, Shams Eldin Ali Hassan A1 - Khang, Young-Ho A1 - Kim, Daniel A1 - Kinfu, Yohannes A1 - Kinge, Jonas M A1 - Kokubo, Yoshihiro A1 - Kosen, Soewarta A1 - Defo, Barthelemy Kuate A1 - Kumar, G Anil A1 - Kumar, Kaushalendra A1 - Kumar, Ravi B A1 - Lai, Taavi A1 - Lan, Qing A1 - Larsson, Anders A1 - Lee, Jong-Tae A1 - Leinsalu, Mall A1 - Lim, Stephen S A1 - Lipshultz, Steven E A1 - Logroscino, Giancarlo A1 - Lotufo, Paulo A A1 - Lunevicius, Raimundas A1 - Lyons, Ronan Anthony A1 - Ma, Stefan A1 - Mahdi, Abbas Ali A1 - Marzan, Melvin Barrientos A1 - Mashal, Mohammad Taufiq A1 - Mazorodze, Tasara T A1 - McGrath, John J A1 - Memish, Ziad A A1 - Mendoza, Walter A1 - Mensah, George A A1 - Meretoja, Atte A1 - Miller, Ted R A1 - Mills, Edward J A1 - Mohammad, Karzan Abdulmuhsin A1 - Mokdad, Ali H A1 - Monasta, Lorenzo A1 - Montico, Marcella A1 - Moore, Ami R A1 - Moschandreas, Joanna A1 - Msemburi, William T A1 - Mueller, Ulrich O A1 - Muszynska, Magdalena M A1 - Naghavi, Mohsen A1 - Naidoo, Kovin S A1 - Narayan, K M Venkat A1 - Nejjari, Chakib A1 - Ng, Marie A1 - de Dieu Ngirabega, Jean A1 - Nieuwenhuijsen, Mark J A1 - Nyakarahuka, Luke A1 - Ohkubo, Takayoshi A1 - Omer, Saad B A1 - Caicedo, Angel J Paternina A1 - Pillay-van Wyk, Victoria A1 - Pope, Dan A1 - Pourmalek, Farshad A1 - Prabhakaran, Dorairaj A1 - Rahman, Sajjad U R A1 - Rana, Saleem M A1 - Reilly, Robert Quentin A1 - Rojas-Rueda, David A1 - Ronfani, Luca A1 - Rushton, Lesley A1 - Saeedi, Mohammad Yahya A1 - Salomon, Joshua A A1 - Sampson, Uchechukwu A1 - Santos, Itamar S A1 - Sawhney, Monika A1 - Schmidt, Jürgen C A1 - Shakh-Nazarova, Marina A1 - She, Jun A1 - Sheikhbahaei, Sara A1 - Shibuya, Kenji A1 - Shin, Hwashin Hyun A1 - Shishani, Kawkab A1 - Shiue, Ivy A1 - Sigfusdottir, Inga Dora A1 - Singh, Jasvinder A A1 - Skirbekk, Vegard A1 - Sliwa, Karen A1 - Soshnikov, Sergey S A1 - Sposato, Luciano A A1 - Stathopoulou, Vasiliki Kalliopi A1 - Stroumpoulis, Konstantinos A1 - Tabb, Karen M A1 - Talongwa, Roberto Tchio A1 - Teixeira, Carolina Maria A1 - Terkawi, Abdullah Sulieman A1 - Thomson, Alan J A1 - Thorne-Lyman, Andrew L A1 - Toyoshima, Hideaki A1 - Dimbuene, Zacharie Tsala A1 - Uwaliraye, Parfait A1 - Uzun, Selen Begüm A1 - Vasankari, Tommi J A1 - Vasconcelos, Ana Maria Nogales A1 - Vlassov, Vasiliy Victorovich A1 - Vollset, Stein Emil A1 - Waller, Stephen A1 - Wan, Xia A1 - Weichenthal, Scott A1 - Weiderpass, Elisabete A1 - Weintraub, Robert G A1 - Westerman, Ronny A1 - Wilkinson, James D A1 - Williams, Hywel C A1 - Yang, Yang C A1 - Yentur, Gokalp Kadri A1 - Yip, Paul A1 - Yonemoto, Naohiro A1 - Younis, Mustafa A1 - Yu, Chuanhua A1 - Jin, Kim Yun A1 - El Sayed Zaki, Maysaa A1 - Zhu, Shankuan A1 - Vos, Theo A1 - Lopez, Alan D A1 - Murray, Christopher J L KW - Child Mortality KW - Child, Preschool KW - Global Health KW - Humans KW - Infant KW - Infant Mortality KW - Infant, Newborn KW - Organizational Objectives KW - Risk Factors KW - Socioeconomic Factors AB -

BACKGROUND: Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.

METHODS: We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.

FINDINGS: We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.

INTERPRETATION: Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.

FUNDING: Bill & Melinda Gates Foundation, US Agency for International Development.

VL - 384 IS - 9947 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24797572?dopt=Abstract ER - TY - JOUR T1 - Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells. JF - Eur J Immunol Y1 - 2014 A1 - Boding, Lasse A1 - Hansen, Ann K A1 - Meroni, Germana A1 - Johansen, Bo B A1 - Braunstein, Thomas H A1 - Bonefeld, Charlotte M A1 - Kongsbak, Martin A1 - Jensen, Benjamin A H A1 - Woetmann, Anders A1 - Thomsen, Allan R A1 - Odum, Niels A1 - von Essen, Marina R A1 - Geisler, Carsten KW - Animals KW - Blotting, Western KW - Cytotoxicity, Immunologic KW - Exocytosis KW - Flow Cytometry KW - Mice KW - Mice, Knockout KW - Mice, Transgenic KW - Proteins KW - Reverse Transcriptase Polymerase Chain Reaction KW - Secretory Vesicles KW - T-Lymphocytes, Cytotoxic AB -

Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2A activity. Loss-of-function mutations in MID1 lead to the X-linked Opitz G/BBB syndrome characterized by defective midline development during embryogenesis. Here, we show that MID1 is strongly upregulated in murine cytotoxic lymphocytes (CTLs), and that it controls TCR signaling, centrosome trafficking, and exocytosis of lytic granules. In accordance, we find that the killing capacity of MID1(-/-) CTLs is impaired. Transfection of MID1 into MID1(-/-) CTLs completely rescued lytic granule exocytosis, and vice versa, knockdown of MID1 inhibited exocytosis of lytic granules in WT CTLs, cementing a central role for MID1 in the regulation of granule exocytosis. Thus, MID1 orchestrates multiple events in CTL responses, adding a novel level of regulation to CTL activation and cytotoxicity.

VL - 44 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25043946?dopt=Abstract ER - TY - JOUR T1 - Neutralizing and IgG antibodies against simian virus 40 in healthy pregnant women in Italy. JF - PLoS One Y1 - 2014 A1 - Comar, Manola A1 - Wong, Connie A1 - Tognon, Mauro A1 - Butel, Janet S AB -

OBJECTIVE: Polyomavirus simian virus 40 (SV40) sequences have been detected in various human specimens and SV40 antibodies have been found in human sera from both healthy individuals and cancer patients. This study analyzed serum samples from healthy pregnant women as well as cord blood samples to determine the prevalence of SV40 antibodies in pregnancy.

METHODS: Serum samples were collected at the time of delivery from two groups of pregnant women as well as cord bloods from one group. The women were born between 1967 and 1993. Samples were assayed by two different serological methods, one group by neutralization of viral infectivity and the other by indirect ELISA employing specific SV40 mimotopes as antigens. Viral DNA assays by real-time polymerase chain reaction were carried out on blood samples.

RESULTS: Neutralization and ELISA tests indicated that the pregnant women were SV40 antibody-positive with overall prevalences of 10.6% (13/123) and 12.7% (14/110), respectively. SV40 neutralizing antibodies were detected in a low number of cord blood samples. Antibody titers were generally low. No viral DNA was detected in either maternal or cord bloods.

CONCLUSIONS: SV40-specific serum antibodies were detected in pregnant women at the time of delivery and in cord bloods. There was no evidence of transplacental transmission of SV40. These data indicate that SV40 is circulating at a low prevalence in the northern Italian population long after the use of contaminated vaccines.

VL - 9 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25335106?dopt=Abstract ER - TY - JOUR T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. JF - Nature Y1 - 2014 A1 - Perry, John R B A1 - Day, Felix A1 - Elks, Cathy E A1 - Sulem, Patrick A1 - Thompson, Deborah J A1 - Ferreira, Teresa A1 - He, Chunyan A1 - Chasman, Daniel I A1 - Esko, Tõnu A1 - Thorleifsson, Gudmar A1 - Albrecht, Eva A1 - Ang, Wei Q A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Feenstra, Bjarke A1 - Franceschini, Nora A1 - Ganna, Andrea A1 - Johnson, Andrew D A1 - Kjellqvist, Sanela A1 - Lunetta, Kathryn L A1 - McMahon, George A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Porcu, Eleonora A1 - Smith, Albert V A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Tšernikova, Natalia A1 - Tikkanen, Emmi A1 - Ulivi, Sheila A1 - Wagner, Erin K A1 - Amin, Najaf A1 - Bierut, Laura J A1 - Byrne, Enda M A1 - Hottenga, Jouke-Jan A1 - Koller, Daniel L A1 - Mangino, Massimo A1 - Pers, Tune H A1 - Yerges-Armstrong, Laura M A1 - Hua Zhao, Jing A1 - Andrulis, Irene L A1 - Anton-Culver, Hoda A1 - Atsma, Femke A1 - Bandinelli, Stefania A1 - Beckmann, Matthias W A1 - Benitez, Javier A1 - Blomqvist, Carl A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Bonanni, Bernardo A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Buring, Julie E A1 - Chang-Claude, Jenny A1 - Chanock, Stephen A1 - Chen, Jinhui A1 - Chenevix-Trench, Georgia A1 - Collée, J Margriet A1 - Couch, Fergus J A1 - Couper, David A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - d'Adamo, Adamo Pio A1 - Davey Smith, George A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dieffenbach, Aida K A1 - Dunning, Alison M A1 - Eiriksdottir, Gudny A1 - Eriksson, Johan G A1 - Fasching, Peter A A1 - Ferrucci, Luigi A1 - Flesch-Janys, Dieter A1 - Flyger, Henrik A1 - Foroud, Tatiana A1 - Franke, Lude A1 - Garcia, Melissa E A1 - García-Closas, Montserrat A1 - Geller, Frank A1 - de Geus, Eco E J A1 - Giles, Graham G A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guenel, Pascal A1 - Guo, Suiqun A1 - Hall, Per A1 - Hamann, Ute A1 - Haring, Robin A1 - Hartman, Catharina A A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank B A1 - Hunter, David J A1 - Karasik, David A1 - Kiel, Douglas P A1 - Knight, Julia A A1 - Kosma, Veli-Matti A1 - Kutalik, Zoltán A1 - Lai, Sandra A1 - Lambrechts, Diether A1 - Lindblom, Annika A1 - Mägi, Reedik A1 - Magnusson, Patrik K A1 - Mannermaa, Arto A1 - Martin, Nicholas G A1 - Masson, Gisli A1 - McArdle, Patrick F A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Milne, Roger L A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Nohr, Ellen A A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Pedersen, Nancy L A1 - Peterlongo, Paolo A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Postma, Dirkje S A1 - Pouta, Anneli A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Ring, Susan A1 - Rivadeneira, Fernando A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rudolph, Anja A1 - Salomaa, Veikko A1 - Sanna, Serena A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Southey, Mellissa C A1 - Sovio, Ulla A1 - Stampfer, Meir J A1 - Stöckl, Doris A1 - Storniolo, Anna M A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan A1 - Visser, Jenny A A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Waeber, Gerard A1 - Waldenberger, Melanie A1 - Wallaschofski, Henri A1 - Wang, Qin A1 - Willemsen, Gonneke A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce H R A1 - Wright, Margaret J A1 - Boomsma, Dorret I A1 - Econs, Michael J A1 - Khaw, Kay-Tee A1 - Loos, Ruth J F A1 - McCarthy, Mark I A1 - Montgomery, Grant W A1 - Rice, John P A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Alizadeh, Behrooz Z A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boyd, Heather A A1 - Crisponi, Laura A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Ingelsson, Erik A1 - Järvelin, Marjo-Riitta A1 - Kraft, Peter A1 - Lawlor, Debbie A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Tim D A1 - Strachan, David P A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Widen, Elisabeth A1 - Zygmunt, Marek A1 - Murray, Anna A1 - Easton, Douglas F A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K KW - Adolescent KW - Age Factors KW - Alleles KW - Body Mass Index KW - Breast Neoplasms KW - Cardiovascular Diseases KW - Child KW - Diabetes Mellitus, Type 2 KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomic Imprinting KW - Humans KW - Hypothalamo-Hypophyseal System KW - Intercellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Menarche KW - Obesity KW - Ovary KW - Parents KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Tandem Pore Domain KW - Proteins KW - Quantitative Trait Loci KW - Receptors, GABA-B KW - Receptors, Retinoic Acid KW - Ribonucleoproteins AB -

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

VL - 514 IS - 7520 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25231870?dopt=Abstract ER - TY - JOUR T1 - Salt-inducible kinase 3, SIK3, is a new gene associated with hearing. JF - Hum Mol Genet Y1 - 2014 A1 - Wolber, Lisa E A1 - Girotto, Giorgia A1 - Buniello, Annalisa A1 - Vuckovic, Dragana A1 - Pirastu, Nicola A1 - Lorente-Cánovas, Beatriz A1 - Rudan, Igor A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Ciullo, Marina A1 - Mangino, Massimo A1 - Steves, Claire A1 - Concas, Maria Pina A1 - Cocca, Massilimiliano A1 - Spector, Tim D A1 - Gasparini, Paolo A1 - Steel, Karen P A1 - Williams, Frances M K KW - Age Factors KW - Animals KW - Cochlea KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Hearing KW - Humans KW - Mice, Inbred C57BL KW - Polymorphism, Single Nucleotide KW - Protein Kinases AB -

Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis. Genome-wide association analyses for PC1-3 were conducted separately in each sample assuming an additive model adjusted for age, sex and relatedness of subjects. Meta-analysis was performed using 2.3 million single-nucleotide polymorphisms (SNPs) tested against each of the three PCs of hearing ability in 4939 individuals. A single SNP lying in intron 6 of the salt-inducible kinase 3 (SIK3) gene was found to be associated with hearing PC2 (P = 3.7×10(-8)) and further supported by whole-genome sequence in a subset. To determine the relevance of this gene in the ear, expression of the Sik3 protein was studied in mouse cochlea of different ages. Sik3 was expressed in murine hair cells during early development and in cells of the spiral ganglion during early development and adulthood. Our results suggest a developmental role of Sik3 in hearing and may be required for the maintenance of adult auditory function.

VL - 23 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25060954?dopt=Abstract ER - TY - JOUR T1 - Spectrum of the mutations in Bernard-Soulier syndrome. JF - Hum Mutat Y1 - 2014 A1 - Savoia, Anna A1 - Kunishima, Shinji A1 - De Rocco, Daniela A1 - Zieger, Barbara A1 - Rand, Margaret L A1 - Pujol-Moix, Núria A1 - Caliskan, Umran A1 - Tokgoz, Huseyin A1 - Pecci, Alessandro A1 - Noris, Patrizia A1 - Srivastava, Alok A1 - Ward, Christopher A1 - Morel-Kopp, Marie-Christine A1 - Alessi, Marie-Christine A1 - Bellucci, Sylvia A1 - Beurrier, Philippe A1 - de Maistre, Emmanuel A1 - Favier, Rémi A1 - Hézard, Nathalie A1 - Hurtaud-Roux, Marie-Françoise A1 - Latger-Cannard, Véronique A1 - Lavenu-Bombled, Cécile A1 - Proulle, Valérie A1 - Meunier, Sandrine A1 - Négrier, Claude A1 - Nurden, Alan A1 - Randrianaivo, Hanitra A1 - Fabris, Fabrizio A1 - Platokouki, Helen A1 - Rosenberg, Nurit A1 - HadjKacem, Basma A1 - Heller, Paula G A1 - Karimi, Mehran A1 - Balduini, Carlo L A1 - Pastore, Annalisa A1 - Lanza, Francois KW - Alleles KW - Bernard-Soulier Syndrome KW - Databases, Nucleic Acid KW - Founder Effect KW - Genetic Variation KW - Humans KW - Mutation KW - Platelet Glycoprotein GPIb-IX Complex KW - Polymorphism, Single Nucleotide KW - von Willebrand Diseases KW - Web Browser AB -

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

VL - 35 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24934643?dopt=Abstract ER - TY - JOUR T1 - Trans-ethnic meta-analysis of white blood cell phenotypes. JF - Hum Mol Genet Y1 - 2014 A1 - Keller, Margaux F A1 - Reiner, Alexander P A1 - Okada, Yukinori A1 - van Rooij, Frank J A A1 - Johnson, Andrew D A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Morris, Andrew P A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Zonderman, Alan B A1 - Lettre, Guillaume A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Bandinelli, Stefania A1 - Qayyum, Rehan A1 - Yanek, Lisa R A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Kooperberg, Charles A1 - Keating, Brendan A1 - Reis, Jared A1 - Tang, Hua A1 - Boerwinkle, Eric A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Nakamura, Yusuke A1 - Kubo, Michiaki A1 - Liu, Simin A1 - Dehghan, Abbas A1 - Felix, Janine F A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Longo, Dan L A1 - Singleton, Andrew B A1 - Psaty, Bruce M A1 - Evans, Michelle K A1 - Cupples, L Adrienne A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Takahashi, Atsushi A1 - Wilson, James G A1 - Ganesh, Santhi K A1 - Nalls, Mike A KW - African Americans KW - Asian Continental Ancestry Group KW - Bayes Theorem KW - European Continental Ancestry Group KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Linkage Disequilibrium KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25096241?dopt=Abstract ER - TY - JOUR T1 - Validation of point-of-care testing for coeliac disease in children in a tertiary hospital in north India. JF - Arch Dis Child Y1 - 2014 A1 - Singh, Prashant A1 - Wadhwa, Nitya A1 - Chaturvedi, Mona K A1 - Bhatia, Vidyut A1 - Saini, Savita A1 - Tandon, Nikhil A1 - Makharia, Govind K A1 - Maki, Markku A1 - Not, Tarcisio A1 - Phillips, Alan A1 - Bhatnagar, Shinjini KW - Adolescent KW - Celiac Disease KW - Child KW - Child, Preschool KW - Cross-Sectional Studies KW - Female KW - Humans KW - India KW - Male KW - Point-of-Care Systems KW - Sensitivity and Specificity KW - Serologic Tests KW - Tertiary Care Centers AB -

OBJECTIVE: Some of the conventional serological tests for coeliac disease (CD) are expensive, time-consuming and not readily available in developing countries, leading to a delay in diagnosis. Recently, point-of-care tests (POCT) have been manufactured and tested in Europe but have not been validated in our setting. We therefore aimed to study the diagnostic accuracy of the POCT 'Biocard' test in diagnosing CD in Indian children.

DESIGN: Cross-sectional study.

SETTING: Tertiary care centre in north India.

PATIENTS: Children, aged 2-18 years, with chronic diarrhoea, short stature or refractory anaemia underwent serological testing for CD with antiendomysial antibodies (AEA), antitissue transglutaminase (tTG) antibodies and Biocard test followed by duodenal biopsy irrespective of serological results. CD was diagnosed with positive AEA and duodenal biopsy showing >grade 2 changes using modified Marsh criteria. Those who were both AEA negative and had normal histology were considered CD negative.

RESULTS: Of 319 children who underwent the serological testing, 170 agreed for biopsy. Of these, 110 were diagnosed with CD and 30 were found to be CD negative. Remaining 30 had discordant AEA and histology results and were not included in analysis. Biocard test agreed with 92/110 positive and 27/30 negative diagnoses based on reference tests (83.6% sensitivity and 90% specificity). tTG was found to be 93.8% sensitive and 96.4% specific.

CONCLUSIONS: We successfully validated the POCT for CD in our setting. It could be used to increase case detection rates in developing countries with a large undiagnosed CD burden.

VL - 99 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24942708?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. JF - Nat Genet Y1 - 2013 A1 - Köttgen, Anna A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Vitart, Veronique A1 - Krumsiek, Jan A1 - Hundertmark, Claudia A1 - Pistis, Giorgio A1 - Ruggiero, Daniela A1 - O'Seaghdha, Conall M A1 - Haller, Toomas A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Johnson, Andrew D A1 - Kutalik, Zoltán A1 - Smith, Albert V A1 - Shi, Julia A1 - Struchalin, Maksim A1 - Middelberg, Rita P S A1 - Brown, Morris J A1 - Gaffo, Angelo L A1 - Pirastu, Nicola A1 - Li, Guo A1 - Hayward, Caroline A1 - Zemunik, Tatijana A1 - Huffman, Jennifer A1 - Yengo, Loic A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Feitosa, Mary F A1 - Liu, Xuan A1 - Malerba, Giovanni A1 - Lopez, Lorna M A1 - van der Harst, Pim A1 - Li, Xinzhong A1 - Kleber, Marcus E A1 - Hicks, Andrew A A1 - Nolte, Ilja M A1 - Johansson, Åsa A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Bakker, Stephan J L A1 - Peden, John F A1 - Dehghan, Abbas A1 - Steri, Maristella A1 - Tenesa, Albert A1 - Lagou, Vasiliki A1 - Salo, Perttu A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Woodward, Owen M A1 - Okada, Yukinori A1 - Tin, Adrienne A1 - Müller, Christian A1 - Oldmeadow, Christopher A1 - Putku, Margus A1 - Czamara, Darina A1 - Kraft, Peter A1 - Frogheri, Laura A1 - Thun, Gian Andri A1 - Grotevendt, Anne A1 - Gislason, Gauti Kjartan A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - McArdle, Patrick A1 - Shuldiner, Alan R A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Schmidt, Helena A1 - Schallert, Michael A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Tanaka, Toshihiro A1 - Munroe, Patricia B A1 - Samani, Nilesh J A1 - Jacobs, David R A1 - Liu, Kiang A1 - d'Adamo, Pio A1 - Ulivi, Sheila A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Campbell, Susan A1 - Devuyst, Olivier A1 - Navarro, Pau A1 - Kolcic, Ivana A1 - Hastie, Nicholas A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Esko, Tõnu A1 - Salumets, Andres A1 - Khaw, Kay Tee A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Isaacs, Aaron A1 - Kraja, Aldi A1 - Zhang, Qunyuan A1 - Wild, Philipp S A1 - Scott, Rodney J A1 - Holliday, Elizabeth G A1 - Org, Elin A1 - Viigimaa, Margus A1 - Bandinelli, Stefania A1 - Metter, Jeffrey E A1 - Lupo, Antonio A1 - Trabetti, Elisabetta A1 - Sorice, Rossella A1 - Döring, Angela A1 - Lattka, Eva A1 - Strauch, Konstantin A1 - Theis, Fabian A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Bruinenberg, Marcel A1 - Stolk, Ronald P A1 - Kooner, Jaspal S A1 - Zhang, Weihua A1 - Winkelmann, Bernhard R A1 - Boehm, Bernhard O A1 - Lucae, Susanne A1 - Penninx, Brenda W A1 - Smit, Johannes H A1 - Curhan, Gary A1 - Mudgal, Poorva A1 - Plenge, Robert M A1 - Portas, Laura A1 - Persico, Ivana A1 - Kirin, Mirna A1 - Wilson, James F A1 - Mateo Leach, Irene A1 - van Gilst, Wiek H A1 - Goel, Anuj A1 - Ongen, Halit A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Imboden, Medea A1 - von Eckardstein, Arnold A1 - Cucca, Francesco A1 - Nagaraja, Ramaiah A1 - Piras, Maria Grazia A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Ernst, Florian A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Prokopenko, Inga A1 - Stumvoll, Michael A1 - Jula, Antti A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Sala, Cinzia A1 - Ridker, Paul M A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Hengstenberg, Christian A1 - Nelson, Christopher P A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Singleton, Andrew B A1 - Kamatani, Naoyuki A1 - Zeller, Tanja A1 - Burnier, Michel A1 - Attia, John A1 - Laan, Maris A1 - Klopp, Norman A1 - Hillege, Hans L A1 - Kloiber, Stefan A1 - Choi, Hyon A1 - Pirastu, Mario A1 - Tore, Silvia A1 - Probst-Hensch, Nicole M A1 - Völzke, Henry A1 - Gudnason, Vilmundur A1 - Parsa, Afshin A1 - Schmidt, Reinhold A1 - Whitfield, John B A1 - Fornage, Myriam A1 - Gasparini, Paolo A1 - Siscovick, David S A1 - Polasek, Ozren A1 - Campbell, Harry A1 - Rudan, Igor A1 - Bouatia-Naji, Nabila A1 - Metspalu, Andres A1 - Loos, Ruth J F A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Wolffenbuttel, Bruce H R A1 - Chambers, John C A1 - März, Winfried A1 - Pramstaller, Peter P A1 - Snieder, Harold A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - Navis, Gerjan A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - Sanna, Serena A1 - Schipf, Sabine A1 - Dunlop, Malcolm G A1 - Tönjes, Anke A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Kao, W H Linda A1 - Ciullo, Marina A1 - Fox, Caroline S A1 - Caulfield, Mark A1 - Bochud, Murielle A1 - Gieger, Christian KW - Analysis of Variance KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Glucose KW - Gout KW - Humans KW - Inhibins KW - Polymorphism, Single Nucleotide KW - Signal Transduction KW - Uric Acid AB -

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract ER - TY - JOUR T1 - Infantile bilateral glaucoma in a child with ectodermal dysplasia. JF - Ophthalmic Genet Y1 - 2013 A1 - Callea, Michele A1 - Vinciguerra, Agatino A1 - Willoughby, Colin E A1 - Deroma, Laura A1 - Clarich, Gabriella KW - Antihypertensive Agents KW - Child KW - Ectodermal Dysplasia KW - Ectodysplasins KW - Humans KW - Hydrophthalmos KW - Intraocular Pressure KW - Male KW - Mutation KW - Polymorphism, Single Nucleotide KW - Tonometry, Ocular AB -

Ectodermal dysplasia is a rare disease which affects at least two ectodermal-derived structures such as hair, nails, skin, sweat glands and teeth. Approximately 200 different conditions have been classified as an ectodermal dysplasia and X-linked hypohidrotic ectodermal dysplasia (XHED) represents the commonest form. Clinically, XHED is characterized by hypotrichosis, hypohidrosis and hypodontia. A variety of ocular manifestations have been reported in XHED, the most common being dryness of eyes due to tear deficiency and instability of the film secondary to the absence of meibomian gland function. Here we report a child with the distinctive clinical features of XHED confirmed with molecular diagnosis who presented with infantile bilateral glaucoma, in addition to the classical ocular involvement in XHED.

VL - 34 IS - 1-2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22428923?dopt=Abstract ER - TY - JOUR T1 - Evidence of inbreeding depression on human height. JF - PLoS Genet Y1 - 2012 A1 - McQuillan, Ruth A1 - Eklund, Niina A1 - Pirastu, Nicola A1 - Kuningas, Maris A1 - McEvoy, Brian P A1 - Esko, Tõnu A1 - Corre, Tanguy A1 - Davies, Gail A1 - Kaakinen, Marika A1 - Lyytikäinen, Leo-Pekka A1 - Kristiansson, Kati A1 - Havulinna, Aki S A1 - Gögele, Martin A1 - Vitart, Veronique A1 - Tenesa, Albert A1 - Aulchenko, Yurii A1 - Hayward, Caroline A1 - Johansson, Åsa A1 - Boban, Mladen A1 - Ulivi, Sheila A1 - Robino, Antonietta A1 - Boraska, Vesna A1 - Igl, Wilmar A1 - Wild, Sarah H A1 - Zgaga, Lina A1 - Amin, Najaf A1 - Theodoratou, Evropi A1 - Polasek, Ozren A1 - Girotto, Giorgia A1 - Lopez, Lorna M A1 - Sala, Cinzia A1 - Lahti, Jari A1 - Laatikainen, Tiina A1 - Prokopenko, Inga A1 - Kals, Mart A1 - Viikari, Jorma A1 - Yang, Jian A1 - Pouta, Anneli A1 - Estrada, Karol A1 - Hofman, Albert A1 - Freimer, Nelson A1 - Martin, Nicholas G A1 - Kähönen, Mika A1 - Milani, Lili A1 - Heliövaara, Markku A1 - Vartiainen, Erkki A1 - Räikkönen, Katri A1 - Masciullo, Corrado A1 - Starr, John M A1 - Hicks, Andrew A A1 - Esposito, Laura A1 - Kolcic, Ivana A1 - Farrington, Susan M A1 - Oostra, Ben A1 - Zemunik, Tatijana A1 - Campbell, Harry A1 - Kirin, Mirna A1 - Pehlic, Marina A1 - Faletra, Flavio A1 - Porteous, David A1 - Pistis, Giorgio A1 - Widen, Elisabeth A1 - Salomaa, Veikko A1 - Koskinen, Seppo A1 - Fischer, Krista A1 - Lehtimäki, Terho A1 - Heath, Andrew A1 - McCarthy, Mark I A1 - Rivadeneira, Fernando A1 - Montgomery, Grant W A1 - Tiemeier, Henning A1 - Hartikainen, Anna-Liisa A1 - Madden, Pamela A F A1 - d'Adamo, Pio A1 - Hastie, Nicholas D A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - van Duijn, Cornelia M A1 - Dunlop, Malcolm A1 - Rudan, Igor A1 - Gasparini, Paolo A1 - Pramstaller, Peter P A1 - Deary, Ian J A1 - Toniolo, Daniela A1 - Eriksson, Johan G A1 - Jula, Antti A1 - Raitakari, Olli T A1 - Metspalu, Andres A1 - Perola, Markus A1 - Järvelin, Marjo-Riitta A1 - Uitterlinden, André A1 - Visscher, Peter M A1 - Wilson, James F KW - Adult KW - Aged KW - Body Height KW - Consanguinity KW - Databases, Genetic KW - Family KW - Female KW - Genes, Recessive KW - Genetic Heterogeneity KW - Genome-Wide Association Study KW - Homozygote KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Quantitative Trait, Heritable AB -

Stature is a classical and highly heritable complex trait, with 80%-90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ(2) = 83.89, df = 1; p = 5.2 × 10(-20)). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.

VL - 8 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22829771?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and functional follow-up reveals new loci for kidney function. JF - PLoS Genet Y1 - 2012 A1 - Pattaro, Cristian A1 - Köttgen, Anna A1 - Teumer, Alexander A1 - Garnaas, Maija A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Åsa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Chouraki, Vincent A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Kollerits, Barbara A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank B A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Döring, Angela A1 - Wichmann, H-Erich A1 - Kolcic, Ivana A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Endlich, Karlhans A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Giulianini, Franco A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Metzger, Marie A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline C M A1 - Hayward, Caroline A1 - Ridker, Paul A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Goessling, Wolfram A1 - Chasman, Daniel I A1 - Kao, W H Linda A1 - Fox, Caroline S KW - African Americans KW - Aged KW - Animals KW - Caspase 9 KW - Cyclin-Dependent Kinases KW - DEAD-box RNA Helicases KW - DNA Helicases KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Gene Knockdown Techniques KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Phosphoric Diester Hydrolases KW - Zebrafish AB -

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479191?dopt=Abstract ER - TY - JOUR T1 - Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function. JF - Hum Mol Genet Y1 - 2012 A1 - Chasman, Daniel I A1 - Fuchsberger, Christian A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Böger, Carsten A A1 - Endlich, Karlhans A1 - Olden, Matthias A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Taliun, Daniel A1 - Li, Man A1 - Gao, Xiaoyi A1 - Gorski, Mathias A1 - Yang, Qiong A1 - Hundertmark, Claudia A1 - Foster, Meredith C A1 - O'Seaghdha, Conall M A1 - Glazer, Nicole A1 - Isaacs, Aaron A1 - Liu, Ching-Ti A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Struchalin, Maksim A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Johnson, Andrew D A1 - Gierman, Hinco J A1 - Feitosa, Mary F A1 - Hwang, Shih-Jen A1 - Atkinson, Elizabeth J A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Johansson, Åsa A1 - Tönjes, Anke A1 - Dehghan, Abbas A1 - Lambert, Jean-Charles A1 - Holliday, Elizabeth G A1 - Sorice, Rossella A1 - Kutalik, Zoltán A1 - Lehtimäki, Terho A1 - Esko, Tõnu A1 - Deshmukh, Harshal A1 - Ulivi, Sheila A1 - Chu, Audrey Y A1 - Murgia, Federico A1 - Trompet, Stella A1 - Imboden, Medea A1 - Coassin, Stefan A1 - Pistis, Giorgio A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Mitchell, Braxton D A1 - Boerwinkle, Eric A1 - Schmidt, Helena A1 - Cavalieri, Margherita A1 - Rao, Madhumathi A1 - Hu, Frank A1 - Demirkan, Ayse A1 - Oostra, Ben A A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Ding, Jingzhong A1 - Andrews, Jeanette S A1 - Freedman, Barry I A1 - Giulianini, Franco A1 - Koenig, Wolfgang A1 - Illig, Thomas A1 - Meisinger, Christa A1 - Gieger, Christian A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Boban, Mladen A1 - Minelli, Cosetta A1 - Wheeler, Heather E A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Nöthlings, Ute A1 - Jacobs, Gunnar A1 - Biffar, Reiner A1 - Ernst, Florian A1 - Homuth, Georg A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Stracke, Sylvia A1 - Völker, Uwe A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Aulchenko, Yurii S A1 - Polasek, Ozren A1 - Hastie, Nick A1 - Vitart, Veronique A1 - Helmer, Catherine A1 - Wang, Jie Jin A1 - Stengel, Bénédicte A1 - Ruggiero, Daniela A1 - Bergmann, Sven A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Nikopensius, Tiit A1 - Province, Michael A1 - Ketkar, Shamika A1 - Colhoun, Helen A1 - Doney, Alex A1 - Robino, Antonietta A1 - Krämer, Bernhard K A1 - Portas, Laura A1 - Ford, Ian A1 - Buckley, Brendan M A1 - Adam, Martin A1 - Thun, Gian-Andri A1 - Paulweber, Bernhard A1 - Haun, Margot A1 - Sala, Cinzia A1 - Mitchell, Paul A1 - Ciullo, Marina A1 - Kim, Stuart K A1 - Vollenweider, Peter A1 - Raitakari, Olli A1 - Metspalu, Andres A1 - Palmer, Colin A1 - Gasparini, Paolo A1 - Pirastu, Mario A1 - Jukema, J Wouter A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Toniolo, Daniela A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Siscovick, David S A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Franke, Andre A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Prokopenko, Inga A1 - Witteman, Jacqueline A1 - Hayward, Caroline A1 - Ridker, Paul M A1 - Parsa, Afshin A1 - Bochud, Murielle A1 - Heid, Iris M A1 - Kao, W H Linda A1 - Fox, Caroline S A1 - Köttgen, Anna KW - Amino Acid Transport Systems, Basic KW - Antigens, CD98 Heavy Chain KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Inhibin-beta Subunits KW - Intracellular Signaling Peptides and Proteins KW - Low Density Lipoprotein Receptor-Related Protein-2 KW - Membrane Proteins KW - Polymorphism, Single Nucleotide AB -

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10(-9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10(-4)-2.2 × 10(-7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.

VL - 21 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22962313?dopt=Abstract ER - TY - JOUR T1 - Lutein and zeaxanthin supplementation in preterm infants to prevent retinopathy of prematurity: a randomized controlled study. JF - J Matern Fetal Neonatal Med Y1 - 2012 A1 - Dani, Carlo A1 - Lori, Ilaria A1 - Favelli, Federica A1 - Frosini, Saverio A1 - Messner, Hubert A1 - Wanker, Petra A1 - De Marini, Sergio A1 - Oretti, Chiara A1 - Boldrini, Antonio A1 - Massimiliano, Ciantelli A1 - Bragetti, Patrizia A1 - Germini, Cristiana KW - Antioxidants KW - Drug Administration Schedule KW - Drug Combinations KW - Female KW - Humans KW - Infant, Newborn KW - Infant, Premature KW - Logistic Models KW - Lutein KW - Male KW - Retinopathy of Prematurity KW - Risk Factors KW - Treatment Outcome KW - Xanthophylls KW - Zeaxanthins AB -

OBJECTIVES: Lutein and its isomer zeaxanthin (L/Z) function in the eye as antioxidant agents and blue-light filters. Our aim was to evaluate whether their administration could help decrease the occurrence of retinopathy of prematurity (ROP) in preterm infants.

METHODS: Infants with gestational age ≤32 weeks were randomly assigned to receive a daily dose of L/Z (0.14 + 0.006 mg) or placebo until discharge.

RESULTS: ROP occurrence was similar in the L/Z (11/58; 19%) and placebo (15/56; 27%) groups, as the occurrence of ROP at each stage and the need of eye surgery.

CONCLUSION: L/Z supplementation was ineffective in preventing ROP in preterm infants and did not affect the outcome at discharge of our patients.

VL - 25 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22003960?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - d'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gerard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations. JF - Nat Genet Y1 - 2012 A1 - Okada, Yukinori A1 - Sim, Xueling A1 - Go, Min Jin A1 - Wu, Jer-Yuarn A1 - Gu, Dongfeng A1 - Takeuchi, Fumihiko A1 - Takahashi, Atsushi A1 - Maeda, Shiro A1 - Tsunoda, Tatsuhiko A1 - Chen, Peng A1 - Lim, Su-Chi A1 - Wong, Tien-Yin A1 - Liu, Jianjun A1 - Young, Terri L A1 - Aung, Tin A1 - Seielstad, Mark A1 - Teo, Yik-Ying A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Han, Bok-Ghee A1 - Kang, Daehee A1 - Chen, Chien-Hsiun A1 - Tsai, Fuu-Jen A1 - Chang, Li-Ching A1 - Fann, S-J Cathy A1 - Mei, Hao A1 - Rao, Dabeeru C A1 - Hixson, James E A1 - Chen, Shufeng A1 - Katsuya, Tomohiro A1 - Isono, Masato A1 - Ogihara, Toshio A1 - Chambers, John C A1 - Zhang, Weihua A1 - Kooner, Jaspal S A1 - Albrecht, Eva A1 - Yamamoto, Kazuhiko A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Kamatani, Naoyuki A1 - Kato, Norihiro A1 - He, Jiang A1 - Chen, Yuan-Tsong A1 - Cho, Yoon Shin A1 - Tai, E-Shyong A1 - Tanaka, Toshihiro KW - Asian Continental Ancestry Group KW - Blood Urea Nitrogen KW - Cohort Studies KW - Creatinine KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Polymorphism, Single Nucleotide KW - Renal Insufficiency, Chronic KW - Uric Acid AB -

Chronic kidney disease (CKD), impairment of kidney function, is a serious public health problem, and the assessment of genetic factors influencing kidney function has substantial clinical relevance. Here, we report a meta-analysis of genome-wide association studies for kidney function-related traits, including 71,149 east Asian individuals from 18 studies in 11 population-, hospital- or family-based cohorts, conducted as part of the Asian Genetic Epidemiology Network (AGEN). Our meta-analysis identified 17 loci newly associated with kidney function-related traits, including the concentrations of blood urea nitrogen, uric acid and serum creatinine and estimated glomerular filtration rate based on serum creatinine levels (eGFRcrea) (P < 5.0 × 10(-8)). We further examined these loci with in silico replication in individuals of European ancestry from the KidneyGen, CKDGen and GUGC consortia, including a combined total of ∼110,347 individuals. We identify pleiotropic associations among these loci with kidney function-related traits and risk of CKD. These findings provide new insights into the genetics of kidney function.

VL - 44 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22797727?dopt=Abstract ER - TY - JOUR T1 - Molecular diagnosis of Usher syndrome: application of two different next generation sequencing-based procedures. JF - PLoS One Y1 - 2012 A1 - Licastro, Danilo A1 - Mutarelli, Margherita A1 - Peluso, Ivana A1 - Neveling, Kornelia A1 - Wieskamp, Nienke A1 - Rispoli, Rossella A1 - Vozzi, Diego A1 - Athanasakis, Emmanouil A1 - D'Eustacchio, Angela A1 - Pizzo, Mariateresa A1 - D'Amico, Francesca A1 - Ziviello, Carmela A1 - Simonelli, Francesca A1 - Fabretto, Antonella A1 - Scheffer, Hans A1 - Gasparini, Paolo A1 - Banfi, Sandro A1 - Nigro, Vincenzo KW - Child, Preschool KW - Exome KW - Genome, Human KW - High-Throughput Nucleotide Sequencing KW - Humans KW - Molecular Diagnostic Techniques KW - Pilot Projects KW - Sequence Analysis, DNA KW - Usher Syndromes AB -

Usher syndrome (USH) is a clinically and genetically heterogeneous disorder characterized by visual and hearing impairments. Clinically, it is subdivided into three subclasses with nine genes identified so far. In the present study, we investigated whether the currently available Next Generation Sequencing (NGS) technologies are already suitable for molecular diagnostics of USH. We analyzed a total of 12 patients, most of which were negative for previously described mutations in known USH genes upon primer extension-based microarray genotyping. We enriched the NGS template either by whole exome capture or by Long-PCR of the known USH genes. The main NGS sequencing platforms were used: SOLiD for whole exome sequencing, Illumina (Genome Analyzer II) and Roche 454 (GS FLX) for the Long-PCR sequencing. Long-PCR targeting was more efficient with up to 94% of USH gene regions displaying an overall coverage higher than 25×, whereas whole exome sequencing yielded a similar coverage for only 50% of those regions. Overall this integrated analysis led to the identification of 11 novel sequence variations in USH genes (2 homozygous and 9 heterozygous) out of 18 detected. However, at least two cases were not genetically solved. Our result highlights the current limitations in the diagnostic use of NGS for USH patients. The limit for whole exome sequencing is linked to the need of a strong coverage and to the correct interpretation of sequence variations with a non obvious, pathogenic role, whereas the targeted approach suffers from the high genetic heterogeneity of USH that may be also caused by the presence of additional causative genes yet to be identified.

VL - 7 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22952768?dopt=Abstract ER - TY - JOUR T1 - Atlanto-axial joint involvement as exclusive manifestation of juvenile idiopathic arthritis (JIA). JF - Clin Exp Rheumatol Y1 - 2011 A1 - Taddio, A A1 - Pellegrin, M C A1 - Gregori, M A1 - Wientroub, S A1 - Padeh, S A1 - Lepore, L KW - Antirheumatic Agents KW - Arthritis, Juvenile KW - Atlanto-Axial Joint KW - Child KW - Dislocations KW - Female KW - Glucocorticoids KW - Humans KW - Magnetic Resonance Imaging KW - Pulse Therapy, Drug KW - Torticollis KW - Treatment Outcome KW - Uveitis VL - 29 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21906438?dopt=Abstract ER - TY - JOUR T1 - Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. JF - Clin Immunol Y1 - 2011 A1 - Mazza, Cinzia A1 - Buzi, Fabio A1 - Ortolani, Federica A1 - Vitali, Alberto A1 - Notarangelo, Lucia D A1 - Weber, Giovanna A1 - Bacchetta, Rosa A1 - Soresina, Annarosa A1 - Lougaris, Vassilios A1 - Greggio, Nella A A1 - Taddio, Andrea A1 - Pasic, Srdjan A1 - de Vroede, Monique A1 - Pac, Malgorzata A1 - Kilic, Sara Sebnem A1 - Ozden, Sanal A1 - Rusconi, Roberto A1 - Martino, Silvana A1 - Capalbo, Donatella A1 - Salerno, Mariacarolina A1 - Pignata, Claudio A1 - Radetti, Giorgio A1 - Maggiore, Giuseppe A1 - Plebani, Alessandro A1 - Notarangelo, Luigi D A1 - Badolato, Raffaele KW - Adolescent KW - Adult KW - Child KW - Child, Preschool KW - Heterozygote KW - Homozygote KW - Humans KW - Middle Aged KW - Mutation KW - Polyendocrinopathies, Autoimmune KW - Time Factors KW - Young Adult AB -

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive organ-specific autoimmune disorder that is characterized by a variable combination of (i) chronic mucocutaneous candidiasis, (ii) polyendocrinopathy and/or hepatitis and (iii) dystrophy of the dental enamel and nails. We analyzed the AIRE (autoimmune regulator) gene in subjects who presented any symptom that has been associated with APECED, including candidiasis and autoimmune endocrinopathy. We observed that 83.3% of patients presented at least two of the three typical manifestations of APECED, while the remaining 16.7% of patients showed other signs of the disease. Analysis of the genetic diagnosis of these subjects revealed that a considerable delay occurs in the majority of patients between the appearance of symptoms and the diagnosis. Overall, the mean diagnostic delay in our patients was 10.2 years. These results suggest that molecular analysis of AIRE should be performed in patients with relapsing mucocutaneous candidiasis for early identification of APECED.

VL - 139 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21295522?dopt=Abstract ER - TY - JOUR T1 - Daily practice of mechanical ventilation in Italian pediatric intensive care units: a prospective survey. JF - Pediatr Crit Care Med Y1 - 2011 A1 - Wolfler, Andrea A1 - Calderoni, Edoardo A1 - Ottonello, Giancarlo A1 - Conti, Giorgio A1 - Baroncini, Simonetta A1 - Santuz, Pierantonio A1 - Vitale, Pasquale A1 - Salvo, Ida KW - Adolescent KW - Child KW - Child, Preschool KW - Clinical Protocols KW - Female KW - Humans KW - Infant KW - Infant, Newborn KW - Intensive Care Units, Pediatric KW - Intubation, Intratracheal KW - Italy KW - Male KW - Prospective Studies KW - Respiration, Artificial KW - Respiratory Insufficiency AB -

OBJECTIVES: To assess how children requiring endotracheal intubation are mechanically ventilated in Italian pediatric intensive care units (PICUs).

DESIGN: A prospective, national, observational, multicenter, 6-month study.

SETTING: Eighteen medical-surgical PICUs.

PATIENTS: A total of 1943 consecutive children, aged 0-16 yrs, admitted between November 1, 2006 and April 30, 2007.

INTERVENTIONS: None.

MEASUREMENTS AND MAIN RESULTS: Data on cause of respiratory failure, length of mechanical ventilation (MV), mode of ventilation, use of specific interventions were recorded for all children requiring endotracheal intubation for >24 hrs. Children were stratified for age, type of patient, and cause of respiratory failure. A total of 956 (49.2%) patients required MV via an endotracheal tube; 673 (34.6%) were ventilated for >24 hrs. The median length of MV was 4.5 days for all patients. If postoperative patients were excluded, the median time was 5 days. Bronchiolitis (6.7%), pneumonia (6.7%), and upper airway obstruction (5.3%) were the most frequent causes of acute respiratory failure, and altered mental status (9.2%) was the most frequent reason for MV. The overall mortality was 6.7% with highest rates for heart disease (nonoperative), sepsis, and acute respiratory distress syndrome (26.1%, 22.2%, and 16.7% respectively). Length of stay, associated chronic disease, severity score on admission, and PICU mortality were significantly higher in children who received MV (p < .05) than in children who did not. Controlled MV and pressure support ventilation + synchronized intermittent mandatory ventilation were the most frequently used modes of ventilatory assistance during PICU stay.

CONCLUSIONS: Mechanical ventilation is frequently used in Italian PICUs with almost one child of two requiring endotracheal intubation. Children treated with MV represent a more severe category of patients than children who are breathing spontaneously. Describing the standard care and how MV is performed in children can be useful for future clinical studies.

VL - 12 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20351615?dopt=Abstract ER - TY - JOUR T1 - ESPGHAN's 2008 recommendation for early introduction of complementary foods: how good is the evidence? JF - Matern Child Nutr Y1 - 2011 A1 - Cattaneo, Adriano A1 - Williams, Carol A1 - Pallás-Alonso, Carmen Rosa A1 - Hernández-Aguilar, Maria Teresa A1 - Lasarte-Velillas, Juan José A1 - Landa-Rivera, Leonardo A1 - Rouw, Elien A1 - Pina, Mónica A1 - Volta, Alessandro A1 - Oudesluys-Murphy, Anne Marie KW - Breast Feeding KW - Evidence-Based Practice KW - Humans KW - Infant KW - Infant Food KW - Infant Nutritional Physiological Phenomena KW - Milk, Human KW - Nutritional Status KW - Public Health KW - Reproducibility of Results KW - World Health Organization AB -

Since 2002, the World Health Organization and many governments and professional associations have recommended exclusive breastfeeding for 6 months followed by complementary feeding (giving solid foods alongside breast milk) as optimal infant feeding practice. Several articles have been published challenging this recommendation. Arguably, the most influential has been the 2008 commentary of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition, which recommended that complementary foods should be introduced to all infants between 17 and 26 weeks. We challenge the validity of ESPGHAN's position, questioning the adequacy of the literature search, the interpretation and evidence used to reach their conclusions and the balance of an approach that focuses on disease prevention, with scant consideration of growth and neuromotor development. We contend that ESPGHAN's position should be understood as an expert opinion that may be influenced by conflicts of interest. In our view, the ESPGHAN position paper is not evidence based and does not justify a change of the current public health recommendation for 6 months of exclusive breastfeeding. At an individual level, health professionals should understand that developmental readiness for starting solid foods has an age range like other developmental milestones; that fewer infants will probably be ready to start complementary feeding before, rather than after, 6 months; and that their role is to equip parents with the confidence and skills to recognise the signs of developmental readiness. This empowerment process for infants and parents should be preferred over the prescriptive ESPGHAN approach.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21902806?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. JF - Nat Genet Y1 - 2011 A1 - Wain, Louise V A1 - Verwoert, Germaine C A1 - O'Reilly, Paul F A1 - Shi, Gang A1 - Johnson, Toby A1 - Johnson, Andrew D A1 - Bochud, Murielle A1 - Rice, Kenneth M A1 - Henneman, Peter A1 - Smith, Albert V A1 - Ehret, Georg B A1 - Amin, Najaf A1 - Larson, Martin G A1 - Mooser, Vincent A1 - Hadley, David A1 - Dörr, Marcus A1 - Bis, Joshua C A1 - Aspelund, Thor A1 - Esko, Tõnu A1 - Janssens, A Cecile J W A1 - Zhao, Jing Hua A1 - Heath, Simon A1 - Laan, Maris A1 - Fu, Jingyuan A1 - Pistis, Giorgio A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Lucas, Gavin A1 - Pirastu, Nicola A1 - Pichler, Irene A1 - Jackson, Anne U A1 - Webster, Rebecca J A1 - Zhang, Feng A1 - Peden, John F A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Campbell, Harry A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Hottenga, Jouke-Jan A1 - Vitart, Veronique A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Bragg-Gresham, Jennifer L A1 - Alizadeh, Behrooz Z A1 - Chambers, John C A1 - Guo, Xiuqing A1 - Lehtimäki, Terho A1 - Kuhnel, Brigitte A1 - Lopez, Lorna M A1 - Polasek, Ozren A1 - Boban, Mladen A1 - Nelson, Christopher P A1 - Morrison, Alanna C A1 - Pihur, Vasyl A1 - Ganesh, Santhi K A1 - Hofman, Albert A1 - Kundu, Suman A1 - Mattace-Raso, Francesco U S A1 - Rivadeneira, Fernando A1 - Sijbrands, Eric J G A1 - Uitterlinden, André G A1 - Hwang, Shih-Jen A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Zitting, Paavo A1 - McArdle, Wendy L A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Glazer, Nicole L A1 - Taylor, Kent D A1 - Harris, Tamara B A1 - Alavere, Helene A1 - Haller, Toomas A1 - Keis, Aime A1 - Tammesoo, Mari-Liis A1 - Aulchenko, Yurii A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Eyheramendy, Susana A1 - Org, Elin A1 - Sõber, Siim A1 - Lu, Xiaowen A1 - Nolte, Ilja M A1 - Penninx, Brenda W A1 - Corre, Tanguy A1 - Masciullo, Corrado A1 - Sala, Cinzia A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Melander, Olle A1 - O'Donnell, Christopher J A1 - Salomaa, Veikko A1 - d'Adamo, Adamo Pio A1 - Fabretto, Antonella A1 - Faletra, Flavio A1 - Ulivi, Sheila A1 - Del Greco, Fabiola M A1 - Facheris, Maurizio A1 - Collins, Francis S A1 - Bergman, Richard N A1 - Beilby, John P A1 - Hung, Joseph A1 - Musk, A William A1 - Mangino, Massimo A1 - Shin, So-Youn A1 - Soranzo, Nicole A1 - Watkins, Hugh A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Gider, Pierre A1 - Loitfelder, Marisa A1 - Zeginigg, Marion A1 - Hernandez, Dena A1 - Najjar, Samer S A1 - Navarro, Pau A1 - Wild, Sarah H A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - de Geus, Eco J C A1 - Willemsen, Gonneke A1 - Parker, Alex N A1 - Rose, Lynda M A1 - Buckley, Brendan A1 - Stott, David A1 - Orru, Marco A1 - Uda, Manuela A1 - van der Klauw, Melanie M A1 - Zhang, Weihua A1 - Li, Xinzhong A1 - Scott, James A1 - Chen, Yii-Der Ida A1 - Burke, Gregory L A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Döring, Angela A1 - Meitinger, Thomas A1 - Davies, Gail A1 - Starr, John M A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Lindeman, Jan H A1 - Hoen, Peter A C 't A1 - König, Inke R A1 - Felix, Janine F A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Breteler, Monique A1 - Debette, Stéphanie A1 - Destefano, Anita L A1 - Fornage, Myriam A1 - Mitchell, Gary F A1 - Smith, Nicholas L A1 - Holm, Hilma A1 - Stefansson, Kari A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Samani, Nilesh J A1 - Preuss, Michael A1 - Rudan, Igor A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Wichmann, H-Erich A1 - Raitakari, Olli T A1 - Palmas, Walter A1 - Kooner, Jaspal S A1 - Stolk, Ronald P A1 - Jukema, J Wouter A1 - Wright, Alan F A1 - Boomsma, Dorret I A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Schmidt, Reinhold A1 - Farrall, Martin A1 - Spector, Tim D A1 - Palmer, Lyle J A1 - Tuomilehto, Jaakko A1 - Pfeufer, Arne A1 - Gasparini, Paolo A1 - Siscovick, David A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Toniolo, Daniela A1 - Snieder, Harold A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Wareham, Nicholas J A1 - Oostra, Ben A A1 - Metspalu, Andres A1 - Launer, Lenore A1 - Rettig, Rainer A1 - Strachan, David P A1 - Beckmann, Jacques S A1 - Witteman, Jacqueline C M A1 - Erdmann, Jeanette A1 - van Dijk, Ko Willems A1 - Boerwinkle, Eric A1 - Boehnke, Michael A1 - Ridker, Paul M A1 - Järvelin, Marjo-Riitta A1 - Chakravarti, Aravinda A1 - Abecasis, Goncalo R A1 - Gudnason, Vilmundur A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Caulfield, Mark J A1 - Rao, Dabeeru C A1 - Tobin, Martin D A1 - Elliott, Paul A1 - van Duijn, Cornelia M KW - Arteries KW - Blood Pressure KW - Case-Control Studies KW - Follow-Up Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide AB -

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract ER - TY - JOUR T1 - "GINEXMAL RCT: Induction of labour versus expectant management in gestational diabetes pregnancies". JF - BMC Pregnancy Childbirth Y1 - 2011 A1 - Maso, Gianpaolo A1 - Alberico, Salvatore A1 - Wiesenfeld, Uri A1 - Ronfani, Luca A1 - Erenbourg, Anna A1 - Hadar, Eran A1 - Yogev, Yariv A1 - Hod, Moshe KW - Adolescent KW - Adult KW - Cesarean Section KW - Diabetes, Gestational KW - Female KW - Gestational Age KW - Humans KW - Intention to Treat Analysis KW - Labor, Induced KW - Patient Selection KW - Pregnancy KW - Pregnancy Outcome KW - Research Design KW - Watchful Waiting KW - Young Adult AB -

BACKGROUND: Gestational diabetes (GDM) is one of the most common complications of pregnancies affecting around 7% of women. This clinical condition is associated with an increased risk of developing fetal macrosomia and is related to a higher incidence of caesarean section in comparison to the general population. Strong evidence indicating the best management between induction of labour at term and expectant monitoring are missing.

METHODS/DESIGN: Pregnant women with singleton pregnancy in vertex presentation previously diagnosed with gestational diabetes will be asked to participate in a multicenter open-label randomized controlled trial between 38+0 and 39+0 gestational weeks. Women will be recruited in the third trimester in the outpatient clinic or in the Day Assessment Unit according to local protocols. Women who opt to take part will be randomized according to induction of labour or expectant management for spontaneous delivery. Patients allocated to the induction group will be admitted to the obstetric ward and offered induction of labour via use of prostaglandins, Foley catheter or oxytocin (depending on clinical conditions). Women assigned to the expectant arm will be sent to their domicile where they will be followed up until delivery, through maternal and fetal wellbeing monitoring twice weekly. The primary study outcome is the Caesarean section (C-section) rate, whilst secondary measurements are maternal and neonatal outcomes. A total sample of 1760 women (880 each arm) will be recruited to identify a relative difference between the two arms equal to 20% in favour of induction, with concerns to C-section rate. Data will be collected until mothers and newborns discharge from the hospital. Analysis of the outcome measures will be carried out by intention to treat.

DISCUSSION: The present trial will provide evidence as to whether or not, in women affected by gestational diabetes, induction of labour between 38+0 and 39+0 weeks is an effective management to ameliorate maternal and neonatal outcomes. The primary objective is to determine whether caesarean section rate could be reduced among women undergoing induction of labour, in comparison to patients allocated to expectant monitoring. The secondary objective consists of the assessment and comparison of maternal and neonatal outcomes in the two study arms. .

VL - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21507262?dopt=Abstract ER - TY - JOUR T1 - Hearing function and thresholds: a genome-wide association study in European isolated populations identifies new loci and pathways. JF - J Med Genet Y1 - 2011 A1 - Girotto, Giorgia A1 - Pirastu, Nicola A1 - Sorice, Rossella A1 - Biino, Ginevra A1 - Campbell, Harry A1 - d'Adamo, Adamo P A1 - Hastie, Nicholas D A1 - Nutile, Teresa A1 - Polasek, Ozren A1 - Portas, Laura A1 - Rudan, Igor A1 - Ulivi, Sheila A1 - Zemunik, Tatijana A1 - Wright, Alan F A1 - Ciullo, Marina A1 - Hayward, Caroline A1 - Pirastu, Mario A1 - Gasparini, Paolo KW - Adaptor Proteins, Signal Transducing KW - Animals KW - Auditory Threshold KW - Carrier Proteins KW - Databases, Genetic KW - Europe KW - European Continental Ancestry Group KW - Female KW - Founder Effect KW - Genetic Linkage KW - Genome-Wide Association Study KW - Hearing KW - Hearing Loss KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Male KW - Mice KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Protein-Serine-Threonine Kinases KW - Receptor-Like Protein Tyrosine Phosphatases, Class 2 KW - Receptors, Metabotropic Glutamate AB -

BACKGROUND: Hearing is a complex trait, but until now only a few genes are known to contribute to variability of this process. In order to discover genes and pathways that underlie auditory function, a genome-wide association study was carried out within the International Consortium G-EAR.

METHODS: Meta-analysis of genome-wide association study's data from six isolated populations of European ancestry for an overall number of 3417 individuals.

RESULTS: Eight suggestive significant loci (p<10(-7)) were detected with a series of genes expressed within the inner ear such as: DCLK1, PTPRD, GRM8, CMIP. Additional biological candidates marked by a single nucleotide polymorphism (SNP) with a suggestive association (p<10(-6)) were identified, as well as loci encompassing 'gene desert regions'-genes of unknown function or genes whose function has not be linked to hearing so far. Some of these new loci map to already known hereditary hearing loss loci whose genes still need to be identified. Data have also been used to construct a highly significant 'in silico' pathway for hearing function characterised by a network of 49 genes, 34 of which are certainly expressed in the ear.

CONCLUSION: These results provide new insights into the molecular basis of hearing function and may suggest new targets for hearing impairment treatment and prevention.

VL - 48 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21493956?dopt=Abstract ER - TY - JOUR T1 - Multiple loci are associated with white blood cell phenotypes. JF - PLoS Genet Y1 - 2011 A1 - Nalls, Michael A A1 - Couper, David J A1 - Tanaka, Toshiko A1 - van Rooij, Frank J A A1 - Chen, Ming-Huei A1 - Smith, Albert V A1 - Toniolo, Daniela A1 - Zakai, Neil A A1 - Yang, Qiong A1 - Greinacher, Andreas A1 - Wood, Andrew R A1 - Garcia, Melissa A1 - Gasparini, Paolo A1 - Liu, Yongmei A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - Reiner, Alex P A1 - Gieger, Christian A1 - Lagou, Vasiliki A1 - Felix, Janine F A1 - Völzke, Henry A1 - Gouskova, Natalia A A1 - Biffi, Alessandro A1 - Döring, Angela A1 - Völker, Uwe A1 - Chong, Sean A1 - Wiggins, Kerri L A1 - Rendon, Augusto A1 - Dehghan, Abbas A1 - Moore, Matt A1 - Taylor, Kent A1 - Wilson, James G A1 - Lettre, Guillaume A1 - Hofman, Albert A1 - Bis, Joshua C A1 - Pirastu, Nicola A1 - Fox, Caroline S A1 - Meisinger, Christa A1 - Sambrook, Jennifer A1 - Arepalli, Sampath A1 - Nauck, Matthias A1 - Prokisch, Holger A1 - Stephens, Jonathan A1 - Glazer, Nicole L A1 - Cupples, L Adrienne A1 - Okada, Yukinori A1 - Takahashi, Atsushi A1 - Kamatani, Yoichiro A1 - Matsuda, Koichi A1 - Tsunoda, Tatsuhiko A1 - Tanaka, Toshihiro A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Yamamoto, Kazuhiko A1 - Kamatani, Naoyuki A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Prokopenko, Inga A1 - Illig, Thomas A1 - Patel, Kushang V A1 - Garner, Stephen F A1 - Kuhnel, Brigitte A1 - Mangino, Massimo A1 - Oostra, Ben A A1 - Thein, Swee Lay A1 - Coresh, Josef A1 - Wichmann, H-Erich A1 - Menzel, Stephan A1 - Lin, JingPing A1 - Pistis, Giorgio A1 - Uitterlinden, André G A1 - Spector, Tim D A1 - Teumer, Alexander A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Bandinelli, Stefania A1 - Frayling, Timothy M A1 - Chakravarti, Aravinda A1 - van Duijn, Cornelia M A1 - Melzer, David A1 - Ouwehand, Willem H A1 - Levy, Daniel A1 - Boerwinkle, Eric A1 - Singleton, Andrew B A1 - Hernandez, Dena G A1 - Longo, Dan L A1 - Soranzo, Nicole A1 - Witteman, Jacqueline C M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Harris, Tamara B A1 - O'Donnell, Christopher J A1 - Ganesh, Santhi K KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Leukocyte Count KW - Leukocytes KW - Molecular Epidemiology KW - Multigene Family KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Ubiquitin-Protein Ligases AB -

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21738480?dopt=Abstract ER - TY - JOUR T1 - Osteoprotegerin promotes vascular fibrosis via a TGF-β1 autocrine loop. JF - Atherosclerosis Y1 - 2011 A1 - Toffoli, Barbara A1 - Pickering, Raelene J A1 - Tsorotes, Despina A1 - Wang, Bo A1 - Bernardi, Stella A1 - Kantharidis, Phillip A1 - Fabris, Bruno A1 - Zauli, Giorgio A1 - Secchiero, Paola A1 - Thomas, Merlin C KW - Animals KW - Apolipoproteins E KW - Cell Proliferation KW - Collagen KW - Fibronectins KW - Fibrosis KW - Gene Expression Regulation KW - Humans KW - Mice KW - Mice, Inbred C57BL KW - Mice, Transgenic KW - Muscle, Smooth, Vascular KW - Myocytes, Smooth Muscle KW - Osteoprotegerin KW - Platelet-Derived Growth Factor KW - Transforming Growth Factor beta1 AB -

BACKGROUND: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis.

METHODS: Aortic samples were analyzed after in vivo treatment of ApoE(-/-) mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-β1 (TGF-β1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-β1, platelet derived growth factor (PDGF) and angiogensin II (Ang II).

RESULTS: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-β1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-β1. On the other hand, exposure to recombinant TGF-β1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC.

CONCLUSIONS: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-β1 and OPG.

VL - 218 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21679949?dopt=Abstract ER - TY - JOUR T1 - Setting research priorities to reduce global mortality from childhood pneumonia by 2015. JF - PLoS Med Y1 - 2011 A1 - Rudan, Igor A1 - El Arifeen, Shams A1 - Bhutta, Zulfiqar A A1 - Black, Robert E A1 - Brooks, Abdullah A1 - Chan, Kit Yee A1 - Chopra, Mickey A1 - Duke, Trevor A1 - Marsh, David A1 - Pio, Antonio A1 - Simoes, Eric A F A1 - Tamburlini, Giorgio A1 - Theodoratou, Evropi A1 - Weber, Martin W A1 - Whitney, Cynthia G A1 - Campbell, Harry A1 - Qazi, Shamim A KW - Biomedical Research KW - Child, Preschool KW - Humans KW - Infant KW - Infant, Newborn KW - Pneumonia VL - 8 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21980266?dopt=Abstract ER - TY - JOUR T1 - Therapeutic approaches in the treatment of juvenile dermatomyositis in patients with recent-onset disease and in those experiencing disease flare: an international multicenter PRINTO study. JF - Arthritis Rheum Y1 - 2011 A1 - Hasija, Rachana A1 - Pistorio, Angela A1 - Ravelli, Angelo A1 - Demirkaya, Erkan A1 - Khubchandani, Raju A1 - Guseinova, Dinara A1 - Malattia, Clara A1 - Canhao, Helena A1 - Harel, Liora A1 - Foell, Dirk A1 - Wouters, Carine A1 - De Cunto, Carmen A1 - Huemer, Christian A1 - Kimura, Yukiko A1 - Mangge, Harald A1 - Minetti, Carlo A1 - Nordal, Ellen Berit A1 - Philippet, Pierre A1 - Garozzo, Rosaria A1 - Martini, Alberto A1 - Ruperto, Nicolino KW - Adolescent KW - Adrenal Cortex Hormones KW - Child KW - Dermatologic Agents KW - Dermatomyositis KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Methotrexate KW - Prospective Studies KW - Treatment Outcome AB -

OBJECTIVE: To evaluate response to therapy over a 24-month period in a large prospective international cohort of patients with juvenile dermatomyositis (DM).

METHODS: The study included 145 patients with recent-onset juvenile DM and 130 juvenile DM patients experiencing disease flare, all of whom were <18 years old. Disease activity parameters and therapeutic approaches in 4 geographic areas were analyzed at baseline and at 6, 12, and 24 months. Response was assessed according to the Pediatric Rheumatology International Trials Organization (PRINTO) juvenile DM response criteria, and data were reported "as observed" and in the intent-to-treat (ITT) population.

RESULTS: Patients with recent-onset juvenile DM at baseline had higher baseline disease activity and greater improvement over 24 months when compared to juvenile DM patients experiencing disease flare at baseline. Methotrexate (MTX) or high-dose corticosteroids were administered more frequently to patients with recent-onset juvenile DM, compared to juvenile DM patients experiencing disease flare, who were more likely to receive cyclosporine. Compared to patients from Western and Eastern Europe, a higher proportion of patients from South and Central America and North America received pulse steroids, and the average steroid dosage was higher in the North American and South and Central American patients. The use of MTX was similar in all 4 regions, while cyclosporin A was more frequently used in Western Europe. In the "as observed" analysis, 57.9% of the patients with recent-onset juvenile DM and 36.4% of the patients experiencing disease flare (P<0.001) reached at least a 70% response by PRINTO criteria at 6 months; these proportions had increased at month 24 to 78.4% and 51.2%, respectively (P<0.001). Corresponding results of the ITT analysis were much lower, with only one-third of the patients able to maintain the initial assigned therapy over 24 months.

CONCLUSION: Patients with recent-onset juvenile DM are more likely to achieve significant clinical improvement over 24 months, when compared to patients experiencing flares of juvenile DM. Internationally, various therapeutic approaches are used to treat this disease.

VL - 63 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21647864?dopt=Abstract ER - TY - JOUR T1 - Abatacept improves health-related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis. JF - Arthritis Care Res (Hoboken) Y1 - 2010 A1 - Ruperto, Nicolino A1 - Lovell, Daniel J A1 - Li, Tracy A1 - Sztajnbok, Flavio A1 - Goldenstein-Schainberg, Claudia A1 - Scheinberg, Morton A1 - Penades, Inmaculada Calvo A1 - Fischbach, Michael A1 - Alcala, Javier Orozco A1 - Hashkes, Philip J A1 - Hom, Christine A1 - Jung, Lawrence A1 - Lepore, Loredana A1 - Oliveira, Sheila A1 - Wallace, Carol A1 - Alessio, Maria A1 - Quartier, Pierre A1 - Cortis, Elisabetta A1 - Eberhard, Anne A1 - Simonini, Gabriele A1 - Lemelle, Irene A1 - Chalom, Elizabeth Candell A1 - Sigal, Leonard H A1 - Block, Alan A1 - Covucci, Allison A1 - Nys, Marleen A1 - Martini, Alberto A1 - Giannini, Edward H KW - Adolescent KW - Arthritis, Juvenile KW - Child KW - Double-Blind Method KW - Female KW - Health Status KW - Humans KW - Immunoconjugates KW - Male KW - Pain KW - Quality of Life KW - Questionnaires KW - Sleep Stages AB -

OBJECTIVE: To assess health-related quality of life (HRQOL) in abatacept-treated children/adolescents with juvenile idiopathic arthritis (JIA).

METHODS: In this phase III, double-blind, placebo-controlled trial, subjects with active polyarticular course JIA and an inadequate response/intolerance to ≥1 disease-modifying antirheumatic drug (including biologics) received abatacept 10 mg/kg plus methotrexate (MTX) during the 4-month open-label period (period A). Subjects achieving the American College of Rheumatology Pediatric 30 criteria for improvement (defined "responders") were randomized to abatacept or placebo (plus MTX) in the 6-month double-blind withdrawal period (period B). HRQOL assessments included 15 Child Health Questionnaire (CHQ) health concepts plus the physical (PhS) and psychosocial summary scores (PsS), pain (100-mm visual analog scale), the Children's Sleep Habits Questionnaire, and a daily activity participation questionnaire.

RESULTS: A total of 190 subjects from period A and 122 from period B were eligible for analysis. In period A, there were substantial improvements across all of the CHQ domains (greatest improvement was in pain/discomfort) and the PhS (8.3 units) and PsS (4.3 units) with abatacept. At the end of period B, abatacept-treated subjects had greater improvements versus placebo in all domains (except behavior) and both summary scores. Similar improvement patterns were seen with pain and sleep. For participation in daily activities, an additional 2.6 school days/month and 2.3 parents' usual activity days/month were gained in period A responders with abatacept, and further gains were made in period B (1.9 versus 0.9 [P = 0.033] and 0.2 versus -1.3 [P = 0.109] school days/month and parents' usual activity days/month, respectively, in abatacept- versus placebo-treated subjects).

CONCLUSION: Improvements in HRQOL were observed with abatacept, providing real-life tangible benefits to children with JIA and their parents/caregivers.

VL - 62 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20597110?dopt=Abstract ER - TY - JOUR T1 - Development of paediatric quality of inpatient care indicators for low-income countries - A Delphi study. JF - BMC Pediatr Y1 - 2010 A1 - Ntoburi, Stephen A1 - Hutchings, Andrew A1 - Sanderson, Colin A1 - Carpenter, James A1 - Weber, Martin A1 - English, Mike KW - Child KW - Child, Hospitalized KW - Delphi Technique KW - Developing Countries KW - Expert Testimony KW - Female KW - Humans KW - Inpatients KW - Male KW - Pediatrics KW - Quality Indicators, Health Care KW - World Health Organization AB -

BACKGROUND: Indicators of quality of care for children in hospitals in low-income countries have been proposed, but information on their perceived validity and acceptability is lacking.

METHODS: Potential indicators representing structural and process aspects of care for six common conditions were selected from existing, largely qualitative WHO assessment tools and guidelines. We employed the Delphi technique, which combines expert opinion and existing scientific information, to assess their perceived validity and acceptability. Panels of experts, one representing an international panel and one a national (Kenyan) panel, were asked to rate the indicators over 3 rounds and 2 rounds respectively according to a variety of attributes.

RESULTS: Based on a pre-specified consensus criteria most of the indicators presented to the experts were accepted: 112/137(82%) and 94/133(71%) for the international and local panels respectively. For the other indicators there was no consensus; none were rejected. Most indicators were rated highly on link to outcomes, reliability, relevance, actionability and priority but rated more poorly on feasibility of data collection under routine conditions. There was moderate to substantial agreement between the two panels of experts.

CONCLUSIONS: This Delphi study provided evidence for the perceived usefulness of most of a set of measures of quality of hospital care for children proposed for use in low-income countries. However, both international and local experts expressed concerns that data for many process-based indicators may not currently be available. The feasibility of widespread quality assessment and responsiveness of indicators to intervention should be examined as part of continued efforts to improve approaches to informative hospital quality assessment.

VL - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21144065?dopt=Abstract ER - TY - JOUR T1 - Gestational diabetes and fetal growth acceleration: induction of labour versus expectant management. JF - Minerva Ginecol Y1 - 2010 A1 - Alberico, S A1 - Businelli, C A1 - Wiesenfeld, U A1 - Erenbourg, A A1 - Maso, G A1 - Piccoli, M A1 - Ronfani, L KW - Adult KW - Body Mass Index KW - Cesarean Section KW - Diabetes, Gestational KW - Elective Surgical Procedures KW - Female KW - Fetal Development KW - Fetal Macrosomia KW - Gestational Age KW - Humans KW - Incidence KW - Infant, Newborn KW - Italy KW - Labor, Induced KW - Medical Records KW - Obesity KW - Pregnancy KW - Pregnancy Outcome KW - Retrospective Studies KW - Risk Factors KW - Statistics, Nonparametric KW - Watchful Waiting AB -

AIM: The aim of the study was to compare elective induction of labour at 38 weeks versus expectant management in A1 and A2 gestational diabetes (GDM) pregnancies with fetal growth acceleration. Primary outcome of the study was C-section (CS) rate, while secondary outcomes were macrosomia incidence and adverse perinatal outcomes.

METHODS: A retrospective cohort study was carried out. Data were collected between 1996 and 2006 and evaluated through patients' records analysis. Differences between the two study groups were investigated using non-parametric tests for continuous variables and χ2 test for categorical ones.

RESULTS: There was no significant difference between induction and expectant management in terms of caesarean section rate. A trend favoring women in the induction group in terms of incidence of macrosomia and neonatal outcomes was identified, but results were not statistically significant.

CONCLUSION: Labour induction at 38 weeks in GDM patients with fetal growth acceleration does not seem to determine an increased incidence of C-section in comparison to expectant management, particularly in case of maternal obesity.

VL - 62 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21079575?dopt=Abstract ER - TY - JOUR T1 - Methotrexate withdrawal at 6 vs 12 months in juvenile idiopathic arthritis in remission: a randomized clinical trial. JF - JAMA Y1 - 2010 A1 - Foell, Dirk A1 - Wulffraat, Nico A1 - Wedderburn, Lucy R A1 - Wittkowski, Helmut A1 - Frosch, Michael A1 - Gerss, Joachim A1 - Stanevicha, Valda A1 - Mihaylova, Dimitrina A1 - Ferriani, Virginia A1 - Tsakalidou, Florence Kanakoudi A1 - Foeldvari, Ivan A1 - Cuttica, Ruben A1 - Gonzalez, Benito A1 - Ravelli, Angelo A1 - Khubchandani, Raju A1 - Oliveira, Sheila A1 - Armbrust, Wineke A1 - Garay, Stella A1 - Vojinovic, Jelena A1 - Norambuena, Ximena A1 - Gamir, María Luz A1 - García-Consuegra, Julia A1 - Lepore, Loredana A1 - Susic, Gordana A1 - Corona, Fabrizia A1 - Dolezalova, Pavla A1 - Pistorio, Angela A1 - Martini, Alberto A1 - Ruperto, Nicolino A1 - Roth, Johannes KW - Adolescent KW - Antirheumatic Agents KW - Arthritis, Juvenile KW - ATP-Binding Cassette Transporters KW - Calgranulin B KW - Child KW - Child, Preschool KW - Female KW - Humans KW - Infant KW - Male KW - Methotrexate KW - Predictive Value of Tests KW - Prospective Studies KW - Recurrence KW - Remission Induction AB -

CONTEXT: Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions.

OBJECTIVES: To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares.

DESIGN, SETTING, AND PATIENTS: Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined.

INTERVENTION: Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission.

MAIN OUTCOME MEASURES: Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed.

RESULTS: Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1 110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90).

CONCLUSIONS: In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate.

TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN18186313.

VL - 303 IS - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20371785?dopt=Abstract ER - TY - JOUR T1 - MYH9-related disease: Report on five German families and description of a novel mutation. JF - Ann Hematol Y1 - 2010 A1 - Savoia, Anna A1 - Germeshausen, Manuela A1 - De Rocco, Daniela A1 - Henschel, Bettina A1 - Kratz, Christian P A1 - Kuhlen, Michaela A1 - Rath, Bettina A1 - Steuhl, Klaus-Peter A1 - Wermes, Cornelia A1 - Ballmaier, Matthias KW - Adult KW - Aged KW - Child KW - Chromosome Disorders KW - DNA Mutational Analysis KW - Germany KW - Humans KW - Infant KW - Molecular Motor Proteins KW - Mutation KW - Myosin Heavy Chains KW - Young Adult VL - 89 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20221761?dopt=Abstract ER - TY - JOUR T1 - Risk of preterm delivery in relation to maternal use of psychotropic medications during pregnancy: methodological issues. JF - Am J Obstet Gynecol Y1 - 2010 A1 - Erenbourg, Anna A1 - Wiesenfeld, Uri A1 - Ronfani, Luca KW - Benzodiazepines KW - Confounding Factors (Epidemiology) KW - Data Interpretation, Statistical KW - Female KW - Humans KW - Multivariate Analysis KW - Pregnancy KW - Premature Birth KW - Psychotropic Drugs VL - 203 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20541734?dopt=Abstract ER - TY - JOUR T1 - State of the art and recommendations. Kangaroo mother care: application in a high-tech environment. JF - Breastfeed Rev Y1 - 2010 A1 - Nyqvist, K H A1 - Anderson, G C A1 - Bergman, N A1 - Cattaneo, A A1 - Charpak, N A1 - Davanzo, R A1 - Ewald, U A1 - Ludington-Hoe, S A1 - Mendoza, S A1 - Pallás-Allonso, C A1 - Peláez, J G A1 - Sizun, J A1 - Wiström, A M AB -

UNLABELLED: Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low-income settings, the original KMC modelis implemented. This consists of continuous (24 h/day; 7 days/week) and prolonged mother/parent-infant skin-to-skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding and, adequate follow up. In affluent settings, intermittent KMC with sessions of one or a few hours skin-to-skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high-tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC modelin all types of settings was discussed at the 7th International Workshop on KMC Kangaroo Mother Care protocols in high-tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents'role, modification of the NICU environment, performance of care in KMC, and KMCin case of infant instability.

CONCLUSION: Implementation of the original KMC method, with continuous skin-to-skin contact whenever possible, is recommended for application in high-tech environments, although scientific evaluation should continue.

VL - 18 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21226419?dopt=Abstract ER - TY - JOUR T1 - State of the art and recommendations. Kangaroo mother care: application in a high-tech environment. JF - Acta Paediatr Y1 - 2010 A1 - Nyqvist, K H A1 - Anderson, G C A1 - Bergman, N A1 - Cattaneo, A A1 - Charpak, N A1 - Davanzo, R A1 - Ewald, U A1 - Ludington-Hoe, S A1 - Mendoza, S A1 - Pallás-Allonso, C A1 - Peláez, J G A1 - Sizun, J A1 - Widström, A-M KW - Attitude of Health Personnel KW - Female KW - Humans KW - Infant Care KW - Infant, Newborn KW - Intensive Care Units, Neonatal KW - Male KW - Parent-Child Relations KW - Practice Guidelines as Topic KW - Professional-Patient Relations KW - Role KW - Skin KW - Visitors to Patients AB -

UNLABELLED: Since Kangaroo Mother Care (KMC) was developed in Colombia in the 1970s, two trends in clinical application emerged. In low income settings, the original KMC model is implemented. This consists of continuous (24 h/day, 7 days/week) and prolonged mother/parent-infant skin-to-skin contact; early discharge with the infant in the kangaroo position; (ideally) exclusive breastfeeding; and, adequate follow-up. In affluent settings, intermittent KMC with sessions of one or a few hours skin-to-skin contact for a limited period is common. As a result of the increasing evidence of the benefits of KMC for both infants and families in all intensive care settings, KMC in a high-tech environment was chosen as the topic for the first European Conference on KMC, and the clinical implementation of the KMC model in all types of settings was discussed at the 7th International Workshop on KMC. Kangaroo Mother Care protocols in high-tech Neonatal Intensive Care Units (NICU) should specify criteria for initiation, kangaroo position, transfer to/from KMC, transport in kangaroo position, kangaroo nutrition, parents' role, modification of the NICU environment, performance of care in KMC, and KMC in case of infant instability.

CONCLUSION: Implementation of the original KMC method, with continuous skin-to-skin contact whenever possible, is recommended for application in high-tech environments, although scientific evaluation should continue.

VL - 99 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20219028?dopt=Abstract ER - TY - JOUR T1 - Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease. JF - J Allergy Clin Immunol Y1 - 2010 A1 - Freudenberg, Folke A1 - Wintergerst, Uwe A1 - Roesen-Wolff, Angela A1 - Albert, Michael H A1 - Prell, Christine A1 - Strahm, Brigitte A1 - Koletzko, Sibylle A1 - Ehl, Stephan A1 - Roos, Dirk A1 - Tommasini, Alberto A1 - Ventura, Alessandro A1 - Belohradsky, Bernd H A1 - Seger, Reinhard A1 - Roesler, Joachim A1 - Güngör, Tayfun KW - Age of Onset KW - Anti-Bacterial Agents KW - Antibodies, Monoclonal KW - Child KW - Drug Therapy, Combination KW - Gene Deletion KW - Granulomatous Disease, Chronic KW - Humans KW - Inflammatory Bowel Diseases KW - Male KW - NADPH Oxidase KW - Steroids KW - Treatment Outcome KW - Vidarabine VL - 125 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20371400?dopt=Abstract ER - TY - JOUR T1 - Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies. JF - Nat Genet Y1 - 2010 A1 - Elks, Cathy E A1 - Perry, John R B A1 - Sulem, Patrick A1 - Chasman, Daniel I A1 - Franceschini, Nora A1 - He, Chunyan A1 - Lunetta, Kathryn L A1 - Visser, Jenny A A1 - Byrne, Enda M A1 - Cousminer, Diana L A1 - Gudbjartsson, Daniel F A1 - Esko, Tõnu A1 - Feenstra, Bjarke A1 - Hottenga, Jouke-Jan A1 - Koller, Daniel L A1 - Kutalik, Zoltán A1 - Lin, Peng A1 - Mangino, Massimo A1 - Marongiu, Mara A1 - McArdle, Patrick F A1 - Smith, Albert V A1 - Stolk, Lisette A1 - van Wingerden, Sophie H A1 - Zhao, Jing Hua A1 - Albrecht, Eva A1 - Corre, Tanguy A1 - Ingelsson, Erik A1 - Hayward, Caroline A1 - Magnusson, Patrik K E A1 - Smith, Erin N A1 - Ulivi, Shelia A1 - Warrington, Nicole M A1 - Zgaga, Lina A1 - Alavere, Helen A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Barroso, Inês A1 - Berenson, Gerald S A1 - Bergmann, Sven A1 - Blackburn, Hannah A1 - Boerwinkle, Eric A1 - Buring, Julie E A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Wei A1 - Cornelis, Marilyn C A1 - Couper, David A1 - Coviello, Andrea D A1 - d'Adamo, Pio A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Döring, Angela A1 - Smith, George Davey A1 - Easton, Douglas F A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan A1 - Ferrucci, Luigi A1 - Folsom, Aaron R A1 - Foroud, Tatiana A1 - Garcia, Melissa A1 - Gasparini, Paolo A1 - Geller, Frank A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - Hall, Per A1 - Hankinson, Susan E A1 - Ferreli, Liana A1 - Heath, Andrew C A1 - Hernandez, Dena G A1 - Hofman, Albert A1 - Hu, Frank B A1 - Illig, Thomas A1 - Järvelin, Marjo-Riitta A1 - Johnson, Andrew D A1 - Karasik, David A1 - Khaw, Kay-Tee A1 - Kiel, Douglas P A1 - Kilpeläinen, Tuomas O A1 - Kolcic, Ivana A1 - Kraft, Peter A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Li, Shengxu A1 - Liu, Jianjun A1 - Levy, Daniel A1 - Martin, Nicholas G A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Mooser, Vincent A1 - Murray, Jeffrey C A1 - Murray, Sarah S A1 - Nalls, Michael A A1 - Navarro, Pau A1 - Nelis, Mari A1 - Ness, Andrew R A1 - Northstone, Kate A1 - Oostra, Ben A A1 - Peacock, Munro A1 - Palmer, Lyle J A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peltonen, Leena A1 - Pennell, Craig E A1 - Pharoah, Paul A1 - Polasek, Ozren A1 - Plump, Andrew S A1 - Pouta, Anneli A1 - Porcu, Eleonora A1 - Rafnar, Thorunn A1 - Rice, John P A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salomaa, Veikko A1 - Sanna, Serena A1 - Schlessinger, David A1 - Schork, Nicholas J A1 - Scuteri, Angelo A1 - Segrè, Ayellet V A1 - Shuldiner, Alan R A1 - Soranzo, Nicole A1 - Sovio, Ulla A1 - Srinivasan, Sathanur R A1 - Strachan, David P A1 - Tammesoo, Mar-Liis A1 - Tikkanen, Emmi A1 - Toniolo, Daniela A1 - Tsui, Kim A1 - Tryggvadottir, Laufey A1 - Tyrer, Jonathon A1 - Uda, Manuela A1 - van Dam, Rob M A1 - van Meurs, Joyce B J A1 - Vollenweider, Peter A1 - Waeber, Gerard A1 - Wareham, Nicholas J A1 - Waterworth, Dawn M A1 - Weedon, Michael N A1 - Wichmann, H Erich A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wright, Alan F A1 - Young, Lauren A1 - Zhai, Guangju A1 - Zhuang, Wei Vivian A1 - Bierut, Laura J A1 - Boomsma, Dorret I A1 - Boyd, Heather A A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - van Duijn, Cornelia M A1 - Econs, Michael J A1 - Harris, Tamara B A1 - Hunter, David J A1 - Loos, Ruth J F A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Ridker, Paul M A1 - Spector, Tim D A1 - Streeten, Elizabeth A A1 - Stefansson, Kari A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - Widen, Elisabeth A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Murray, Anna KW - Adolescent KW - Aging KW - Body Height KW - Body Size KW - Child KW - DNA Copy Number Variations KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Inheritance Patterns KW - Menarche KW - Obesity KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Time Factors AB -

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

VL - 42 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21102462?dopt=Abstract ER - TY - JOUR T1 - Towards universal Kangaroo Mother Care: recommendations and report from the First European conference and Seventh International Workshop on Kangaroo Mother Care. JF - Acta Paediatr Y1 - 2010 A1 - Nyqvist, K H A1 - Anderson, G C A1 - Bergman, N A1 - Cattaneo, A A1 - Charpak, N A1 - Davanzo, R A1 - Ewald, U A1 - Ibe, O A1 - Ludington-Hoe, S A1 - Mendoza, S A1 - Pallás-Allonso, C A1 - Ruiz Peláez, J G A1 - Sizun, J A1 - Widström, A-M KW - Congresses as Topic KW - Female KW - Global Health KW - Humans KW - Infant Care KW - Infant, Newborn KW - Male KW - Parent-Child Relations KW - Practice Guidelines as Topic KW - Randomized Controlled Trials as Topic KW - Skin AB -

UNLABELLED: The hallmark of Kangaroo Mother Care (KMC) is the kangaroo position: the infant is cared for skin-to-skin vertically between the mother's breasts and below her clothes, 24 h/day, with father/substitute(s) participating as KMC providers. Intermittent KMC (for short periods once or a few times per day, for a variable number of days) is commonly employed in high-tech neonatal intensive care units. These two modalities should be regarded as a progressive adaptation of the mother-infant dyad, ideally towards continuous KMC, starting gradually and progressively with intermittent KMC. The other components in KMC are exclusive breastfeeding (ideally) and early discharge in kangaroo position with strict follow-up. Current evidence allows the following general statements about KMC in affluent and low-income settings: KMC enhances bonding and attachment; reduces maternal postpartum depression symptoms; enhances infant physiologic stability and reduces pain, increases parental sensitivity to infant cues; contributes to the establishment and longer duration of breastfeeding and has positive effects on infant development and infant/parent interaction. Therefore, intrapartum and postnatal care in all types of settings should adhere to a paradigm of nonseparation of infants and their mothers/families. Preterm/low-birth-weight infants should be regarded as extero-gestational foetuses needing skin-to-skin contact to promote maturation.

CONCLUSION: Kangaroo Mother Care should begin as soon as possible after birth, be applied as continuous skin-to-skin contact to the extent that this is possible and appropriate and continue for as long as appropriate.

VL - 99 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20219044?dopt=Abstract ER - TY - JOUR T1 - Atomic models for the polypeptide backbones of myohemerythrin and hemerythrin. JF - Biochem Biophys Res Commun Y1 - 1975 A1 - Hendrickson, W A A1 - Ward, K B KW - Animals KW - Cnidaria KW - Computers KW - Hemerythrin KW - Metalloproteins KW - Models, Molecular KW - Muscle Proteins KW - Protein Conformation KW - Species Specificity VL - 66 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/5?dopt=Abstract ER - TY - JOUR T1 - Effect of chloroquine on cultured fibroblasts: release of lysosomal hydrolases and inhibition of their uptake. JF - Biochem Biophys Res Commun Y1 - 1975 A1 - Wiesmann, U N A1 - DiDonato, S A1 - Herschkowitz, N N KW - Biological Transport KW - Cells, Cultured KW - Cerebroside-Sulfatase KW - Chloroquine KW - Dextrans KW - Fibroblasts KW - Glucuronidase KW - Humans KW - Leukodystrophy, Metachromatic KW - Lysosomes KW - Pinocytosis KW - Skin KW - Sulfatases VL - 66 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/4?dopt=Abstract ER -