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

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.

%B Nat Genet %V 50 %P 1412-1425 %8 2018 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/30224653?dopt=Abstract %R 10.1038/s41588-018-0205-x %0 Journal Article %J Am J Hum Genet %D 2018 %T Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. %A Ligthart, Symen %A Vaez, Ahmad %A Võsa, Urmo %A Stathopoulou, Maria G %A de Vries, Paul S %A Prins, Bram P %A van der Most, Peter J %A Tanaka, Toshiko %A Naderi, Elnaz %A Rose, Lynda M %A Wu, Ying %A Karlsson, Robert %A Barbalic, Maja %A Lin, Honghuang %A Pool, René %A Zhu, Gu %A Macé, Aurélien %A Sidore, Carlo %A Trompet, Stella %A Mangino, Massimo %A Sabater-Lleal, Maria %A Kemp, John P %A Abbasi, Ali %A Kacprowski, Tim %A Verweij, Niek %A Smith, Albert V %A Huang, Tao %A Marzi, Carola %A Feitosa, Mary F %A Lohman, Kurt K %A Kleber, Marcus E %A Milaneschi, Yuri %A Mueller, Christian %A Huq, Mahmudul %A Vlachopoulou, Efthymia %A Lyytikäinen, Leo-Pekka %A Oldmeadow, Christopher %A Deelen, Joris %A Perola, Markus %A Zhao, Jing Hua %A Feenstra, Bjarke %A Amini, Marzyeh %A Lahti, Jari %A Schraut, Katharina E %A Fornage, Myriam %A Suktitipat, Bhoom %A Chen, Wei-Min %A Li, Xiaohui %A Nutile, Teresa %A Malerba, Giovanni %A Luan, Jian'an %A Bak, Tom %A Schork, Nicholas %A del Greco M, Fabiola %A Thiering, Elisabeth %A Mahajan, Anubha %A Marioni, Riccardo E %A Mihailov, Evelin %A Eriksson, Joel %A Ozel, Ayse Bilge %A Zhang, Weihua %A Nethander, Maria %A Cheng, Yu-Ching %A Aslibekyan, Stella %A Ang, Wei %A Gandin, Ilaria %A Yengo, Loic %A Portas, Laura %A Kooperberg, Charles %A Hofer, Edith %A Rajan, Kumar B %A Schurmann, Claudia %A den Hollander, Wouter %A Ahluwalia, Tarunveer S %A Zhao, Jing %A Draisma, Harmen H M %A Ford, Ian %A Timpson, Nicholas %A Teumer, Alexander %A Huang, Hongyan %A Wahl, Simone %A Liu, Yongmei %A Huang, Jie %A Uh, Hae-Won %A Geller, Frank %A Joshi, Peter K %A Yanek, Lisa R %A Trabetti, Elisabetta %A Lehne, Benjamin %A Vozzi, Diego %A Verbanck, Marie %A Biino, Ginevra %A Saba, Yasaman %A Meulenbelt, Ingrid %A O'Connell, Jeff R %A Laakso, Markku %A Giulianini, Franco %A Magnusson, Patrik K E %A Ballantyne, Christie M %A Hottenga, Jouke Jan %A Montgomery, Grant W %A Rivadineira, Fernando %A Rueedi, Rico %A Steri, Maristella %A Herzig, Karl-Heinz %A Stott, David J %A Menni, Cristina %A Frånberg, Mattias %A St Pourcain, Beate %A Felix, Stephan B %A Pers, Tune H %A Bakker, Stephan J L %A Kraft, Peter %A Peters, Annette %A Vaidya, Dhananjay %A Delgado, Graciela %A Smit, Johannes H %A Großmann, Vera %A Sinisalo, Juha %A Seppälä, Ilkka %A Williams, Stephen R %A Holliday, Elizabeth G %A Moed, Matthijs %A Langenberg, Claudia %A Räikkönen, Katri %A Ding, Jingzhong %A Campbell, Harry %A Sale, Michele M %A Chen, Yii-Der I %A James, Alan L %A Ruggiero, Daniela %A Soranzo, Nicole %A Hartman, Catharina A %A Smith, Erin N %A Berenson, Gerald S %A Fuchsberger, Christian %A Hernandez, Dena %A Tiesler, Carla M T %A Giedraitis, Vilmantas %A Liewald, David %A Fischer, Krista %A Mellström, Dan %A Larsson, Anders %A Wang, Yunmei %A Scott, William R %A Lorentzon, Matthias %A Beilby, John %A Ryan, Kathleen A %A Pennell, Craig E %A Vuckovic, Dragana %A Balkau, Beverly %A Concas, Maria Pina %A Schmidt, Reinhold %A Mendes de Leon, Carlos F %A Bottinger, Erwin P %A Kloppenburg, Margreet %A Paternoster, Lavinia %A Boehnke, Michael %A Musk, A W %A Willemsen, Gonneke %A Evans, David M %A Madden, Pamela A F %A Kähönen, Mika %A Kutalik, Zoltán %A Zoledziewska, Magdalena %A Karhunen, Ville %A Kritchevsky, Stephen B %A Sattar, Naveed %A LaChance, Genevieve %A Clarke, Robert %A Harris, Tamara B %A Raitakari, Olli T %A Attia, John R %A van Heemst, Diana %A Kajantie, Eero %A Sorice, Rossella %A Gambaro, Giovanni %A Scott, Robert A %A Hicks, Andrew A %A Ferrucci, Luigi %A Standl, Marie %A Lindgren, Cecilia M %A Starr, John M %A Karlsson, Magnus %A Lind, Lars %A Li, Jun Z %A Chambers, John C %A Mori, Trevor A %A de Geus, Eco J C N %A Heath, Andrew C %A Martin, Nicholas G %A Auvinen, Juha %A Buckley, Brendan M %A de Craen, Anton J M %A Waldenberger, Melanie %A Strauch, Konstantin %A Meitinger, Thomas %A Scott, Rodney J %A McEvoy, Mark %A Beekman, Marian %A Bombieri, Cristina %A Ridker, Paul M %A Mohlke, Karen L %A Pedersen, Nancy L %A Morrison, Alanna C %A Boomsma, Dorret I %A Whitfield, John B %A Strachan, David P %A Hofman, Albert %A Vollenweider, Peter %A Cucca, Francesco %A Järvelin, Marjo-Riitta %A Jukema, J Wouter %A Spector, Tim D %A Hamsten, Anders %A Zeller, Tanja %A Uitterlinden, André G %A Nauck, Matthias %A Gudnason, Vilmundur %A Qi, Lu %A Grallert, Harald %A Borecki, Ingrid B %A Rotter, Jerome I %A März, Winfried %A Wild, Philipp S %A Lokki, Marja-Liisa %A Boyle, Michael %A Salomaa, Veikko %A Melbye, Mads %A Eriksson, Johan G %A Wilson, James F %A Penninx, Brenda W J H %A Becker, Diane M %A Worrall, Bradford B %A Gibson, Greg %A Krauss, Ronald M %A Ciullo, Marina %A Zaza, Gianluigi %A Wareham, Nicholas J %A Oldehinkel, Albertine J %A Palmer, Lyle J %A Murray, Sarah S %A Pramstaller, Peter P %A Bandinelli, Stefania %A Heinrich, Joachim %A Ingelsson, Erik %A Deary, Ian J %A Mägi, Reedik %A Vandenput, Liesbeth %A van der Harst, Pim %A Desch, Karl C %A Kooner, Jaspal S %A Ohlsson, Claes %A Hayward, Caroline %A Lehtimäki, Terho %A Shuldiner, Alan R %A Arnett, Donna K %A Beilin, Lawrence J %A Robino, Antonietta %A Froguel, Philippe %A Pirastu, Mario %A Jess, Tine %A Koenig, Wolfgang %A Loos, Ruth J F %A Evans, Denis A %A Schmidt, Helena %A Smith, George Davey %A Slagboom, P Eline %A Eiriksdottir, Gudny %A Morris, Andrew P %A Psaty, Bruce M %A Tracy, Russell P %A Nolte, Ilja M %A Boerwinkle, Eric %A Visvikis-Siest, Sophie %A Reiner, Alex P %A Gross, Myron %A Bis, Joshua C %A Franke, Lude %A Franco, Oscar H %A Benjamin, Emelia J %A Chasman, Daniel I %A Dupuis, Josée %A Snieder, Harold %A Dehghan, Abbas %A Alizadeh, Behrooz Z %X

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.

%B Am J Hum Genet %V 103 %P 691-706 %8 2018 Nov 01 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/30388399?dopt=Abstract %R 10.1016/j.ajhg.2018.09.009 %0 Journal Article %J Nat Genet %D 2018 %T Genome-wide association meta-analysis of individuals of European ancestry identifies new loci explaining a substantial fraction of hair color variation and heritability. %A Hysi, Pirro G %A Valdes, Ana M %A Liu, Fan %A Furlotte, Nicholas A %A Evans, David M %A Bataille, Veronique %A Visconti, Alessia %A Hemani, Gibran %A McMahon, George %A Ring, Susan M %A Smith, George Davey %A Duffy, David L %A Zhu, Gu %A Gordon, Scott D %A Medland, Sarah E %A Lin, Bochao D %A Willemsen, Gonneke %A Jan Hottenga, Jouke %A Vuckovic, Dragana %A Girotto, Giorgia %A Gandin, Ilaria %A Sala, Cinzia %A Concas, Maria Pina %A Brumat, Marco %A Gasparini, Paolo %A Toniolo, Daniela %A Cocca, Massimiliano %A Robino, Antonietta %A Yazar, Seyhan %A Hewitt, Alex W %A Chen, Yan %A Zeng, Changqing %A Uitterlinden, André G %A Ikram, M Arfan %A Hamer, Merel A %A van Duijn, Cornelia M %A Nijsten, Tamar %A Mackey, David A %A Falchi, Mario %A Boomsma, Dorret I %A Martin, Nicholas G %A Hinds, David A %A Kayser, Manfred %A Spector, Timothy D %X

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.

%B Nat Genet %V 50 %P 652-656 %8 2018 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/29662168?dopt=Abstract %R 10.1038/s41588-018-0100-5 %0 Journal Article %J Am J Hum Genet %D 2018 %T A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. %A Sung, Yun J %A Winkler, Thomas W %A de Las Fuentes, Lisa %A Bentley, Amy R %A Brown, Michael R %A Kraja, Aldi T %A Schwander, Karen %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Lu, Yingchang %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Feitosa, Mary F %A Kilpeläinen, Tuomas O %A Richard, Melissa A %A Noordam, Raymond %A Aslibekyan, Stella %A Aschard, Hugues %A Bartz, Traci M %A Dorajoo, Rajkumar %A Liu, Yongmei %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert Vernon %A Tajuddin, Salman M %A Tayo, Bamidele O %A Warren, Helen R %A Zhao, Wei %A Zhou, Yanhua %A Matoba, Nana %A Sofer, Tamar %A Alver, Maris %A Amini, Marzyeh %A Boissel, Mathilde %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gandin, Ilaria %A Gao, Chuan %A Giulianini, Franco %A Goel, Anuj %A Harris, Sarah E %A Hartwig, Fernando Pires %A Horimoto, Andrea R V R %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Kuhnel, Brigitte %A Leander, Karin %A Lee, Wen-Jane %A Lin, Keng-Hung %A 'an Luan, Jian %A McKenzie, Colin A %A Meian, He %A Nelson, Christopher P %A Rauramaa, Rainer %A Schupf, Nicole %A Scott, Robert A %A Sheu, Wayne H H %A Stančáková, Alena %A Takeuchi, Fumihiko %A van der Most, Peter J %A Varga, Tibor V %A Wang, Heming %A Wang, Yajuan %A Ware, Erin B %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Alfred, Tamuno %A Amin, Najaf %A Arking, Dan %A Aung, Tin %A Barr, R Graham %A Bielak, Lawrence F %A Boerwinkle, Eric %A Bottinger, Erwin P %A Braund, Peter S %A Brody, Jennifer A %A Broeckel, Ulrich %A Cabrera, Claudia P %A Cade, Brian %A Caizheng, Yu %A Campbell, Archie %A Canouil, Mickaël %A Chakravarti, Aravinda %A Chauhan, Ganesh %A Christensen, Kaare %A Cocca, Massimiliano %A Collins, Francis S %A Connell, John M %A de Mutsert, Renée %A de Silva, H Janaka %A Debette, Stéphanie %A Dörr, Marcus %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Evangelou, Evangelos %A Faul, Jessica D %A Fisher, Virginia A %A Forouhi, Nita G %A Franco, Oscar H %A Friedlander, Yechiel %A Gao, He %A Gigante, Bruna %A Graff, Misa %A Gu, C Charles %A Gu, Dongfeng %A Gupta, Preeti %A Hagenaars, Saskia P %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Hofman, Albert %A Howard, Barbara V %A Hunt, Steven %A Irvin, Marguerite R %A Jia, Yucheng %A Joehanes, Roby %A Justice, Anne E %A Katsuya, Tomohiro %A Kaufman, Joel %A Kerrison, Nicola D %A Khor, Chiea Chuen %A Koh, Woon-Puay %A Koistinen, Heikki A %A Komulainen, Pirjo %A Kooperberg, Charles %A Krieger, Jose E %A Kubo, Michiaki %A Kuusisto, Johanna %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lim, Sing Hui %A Lin, Shiow %A Liu, Ching-Ti %A Liu, Jianjun %A Liu, Jingmin %A Liu, Kiang %A Liu, Yeheng %A Loh, Marie %A Lohman, Kurt K %A Long, Jirong %A Louie, Tin %A Mägi, Reedik %A Mahajan, Anubha %A Meitinger, Thomas %A Metspalu, Andres %A Milani, Lili %A Momozawa, Yukihide %A Morris, Andrew P %A Mosley, Thomas H %A Munson, Peter %A Murray, Alison D %A Nalls, Mike A %A Nasri, Ubaydah %A Norris, Jill M %A North, Kari %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Palmer, Nicholette D %A Pankow, James S %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Polasek, Ozren %A Raitakari, Olli T %A Renstrom, Frida %A Rice, Treva K %A Ridker, Paul M %A Robino, Antonietta %A Robinson, Jennifer G %A Rose, Lynda M %A Rudan, Igor %A Sabanayagam, Charumathi %A Salako, Babatunde L %A Sandow, Kevin %A Schmidt, Carsten O %A Schreiner, Pamela J %A Scott, William R %A Seshadri, Sudha %A Sever, Peter %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Uitterlinden, André G %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya X %A Wei, Wen Bin %A Williams, Christine %A Wilson, Gregory %A Wojczynski, Mary K %A Yao, Jie %A Yuan, Jian-Min %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Chen, Yii-Der Ida %A de Faire, Ulf %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Forrester, Terrence %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Horta, Bernardo Lessa %A Hung, Yi-Jen %A Jonas, Jost B %A Kato, Norihiro %A Kooner, Jaspal S %A Laakso, Markku %A Lehtimäki, Terho %A Liang, Kae-Woei %A Magnusson, Patrik K E %A Newman, Anne B %A Oldehinkel, Albertine J %A Pereira, Alexandre C %A Redline, Susan %A Rettig, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Kamatani, Yoichiro %A Laurie, Cathy C %A Bouchard, Claude %A Cooper, Richard S %A Evans, Michele K %A Gudnason, Vilmundur %A Kardia, Sharon L R %A Kritchevsky, Stephen B %A Levy, Daniel %A O'Connell, Jeff R %A Psaty, Bruce M %A van Dam, Rob M %A Sims, Mario %A Arnett, Donna K %A Mook-Kanamori, Dennis O %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A Fornage, Myriam %A Rotimi, Charles N %A Province, Michael A %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Loos, Ruth J F %A Reiner, Alex P %A Rotter, Jerome I %A Zhu, Xiaofeng %A Bierut, Laura J %A Gauderman, W James %A Caulfield, Mark J %A Elliott, Paul %A Rice, Kenneth %A Munroe, Patricia B %A Morrison, Alanna C %A Cupples, L Adrienne %A Rao, Dabeeru C %A Chasman, Daniel I %K Blood Pressure %K Cohort Studies %K Continental Population Groups %K Diastole %K Epistasis, Genetic %K Female %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Male %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %K Reproducibility of Results %K Smoking %K Systole %X

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).

%B Am J Hum Genet %V 102 %P 375-400 %8 2018 03 01 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29455858?dopt=Abstract %R 10.1016/j.ajhg.2018.01.015 %0 Journal Article %J PLoS One %D 2018 %T Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. %A Feitosa, Mary F %A Kraja, Aldi T %A Chasman, Daniel I %A Sung, Yun J %A Winkler, Thomas W %A Ntalla, Ioanna %A Guo, Xiuqing %A Franceschini, Nora %A Cheng, Ching-Yu %A Sim, Xueling %A Vojinovic, Dina %A Marten, Jonathan %A Musani, Solomon K %A Li, Changwei %A Bentley, Amy R %A Brown, Michael R %A Schwander, Karen %A Richard, Melissa A %A Noordam, Raymond %A Aschard, Hugues %A Bartz, Traci M %A Bielak, Lawrence F %A Dorajoo, Rajkumar %A Fisher, Virginia %A Hartwig, Fernando P %A Horimoto, Andrea R V R %A Lohman, Kurt K %A Manning, Alisa K %A Rankinen, Tuomo %A Smith, Albert V %A Tajuddin, Salman M %A Wojczynski, Mary K %A Alver, Maris %A Boissel, Mathilde %A Cai, Qiuyin %A Campbell, Archie %A Chai, Jin Fang %A Chen, Xu %A Divers, Jasmin %A Gao, Chuan %A Goel, Anuj %A Hagemeijer, Yanick %A Harris, Sarah E %A He, Meian %A Hsu, Fang-Chi %A Jackson, Anne U %A Kähönen, Mika %A Kasturiratne, Anuradhani %A Komulainen, Pirjo %A Kuhnel, Brigitte %A Laguzzi, Federica %A Luan, Jian'an %A Matoba, Nana %A Nolte, Ilja M %A Padmanabhan, Sandosh %A Riaz, Muhammad %A Rueedi, Rico %A Robino, Antonietta %A Said, M Abdullah %A Scott, Robert A %A Sofer, Tamar %A Stančáková, Alena %A Takeuchi, Fumihiko %A Tayo, Bamidele O %A van der Most, Peter J %A Varga, Tibor V %A Vitart, Veronique %A Wang, Yajuan %A Ware, Erin B %A Warren, Helen R %A Weiss, Stefan %A Wen, Wanqing %A Yanek, Lisa R %A Zhang, Weihua %A Zhao, Jing Hua %A Afaq, Saima %A Amin, Najaf %A Amini, Marzyeh %A Arking, Dan E %A Aung, Tin %A Boerwinkle, Eric %A Borecki, Ingrid %A Broeckel, Ulrich %A Brown, Morris %A Brumat, Marco %A Burke, Gregory L %A Canouil, Mickaël %A Chakravarti, Aravinda %A Charumathi, Sabanayagam %A Ida Chen, Yii-Der %A Connell, John M %A Correa, Adolfo %A de Las Fuentes, Lisa %A de Mutsert, Renée %A de Silva, H Janaka %A Deng, Xuan %A Ding, Jingzhong %A Duan, Qing %A Eaton, Charles B %A Ehret, Georg %A Eppinga, Ruben N %A Evangelou, Evangelos %A Faul, Jessica D %A Felix, Stephan B %A Forouhi, Nita G %A Forrester, Terrence %A Franco, Oscar H %A Friedlander, Yechiel %A Gandin, Ilaria %A Gao, He %A Ghanbari, Mohsen %A Gigante, Bruna %A Gu, C Charles %A Gu, Dongfeng %A Hagenaars, Saskia P %A Hallmans, Goran %A Harris, Tamara B %A He, Jiang %A Heikkinen, Sami %A Heng, Chew-Kiat %A Hirata, Makoto %A Howard, Barbara V %A Ikram, M Arfan %A John, Ulrich %A Katsuya, Tomohiro %A Khor, Chiea Chuen %A Kilpeläinen, Tuomas O %A Koh, Woon-Puay %A Krieger, Jose E %A Kritchevsky, Stephen B %A Kubo, Michiaki %A Kuusisto, Johanna %A Lakka, Timo A %A Langefeld, Carl D %A Langenberg, Claudia %A Launer, Lenore J %A Lehne, Benjamin %A Lewis, Cora E %A Li, Yize %A Lin, Shiow %A Liu, Jianjun %A Liu, Jingmin %A Loh, Marie %A Louie, Tin %A Mägi, Reedik %A McKenzie, Colin A %A Meitinger, Thomas %A Metspalu, Andres %A Milaneschi, Yuri %A Milani, Lili %A Mohlke, Karen L %A Momozawa, Yukihide %A Nalls, Mike A %A Nelson, Christopher P %A Sotoodehnia, Nona %A Norris, Jill M %A O'Connell, Jeff R %A Palmer, Nicholette D %A Perls, Thomas %A Pedersen, Nancy L %A Peters, Annette %A Peyser, Patricia A %A Poulter, Neil %A Raffel, Leslie J %A Raitakari, Olli T %A Roll, Kathryn %A Rose, Lynda M %A Rosendaal, Frits R %A Rotter, Jerome I %A Schmidt, Carsten O %A Schreiner, Pamela J %A Schupf, Nicole %A Scott, William R %A Sever, Peter S %A Shi, Yuan %A Sidney, Stephen %A Sims, Mario %A Sitlani, Colleen M %A Smith, Jennifer A %A Snieder, Harold %A Starr, John M %A Strauch, Konstantin %A Stringham, Heather M %A Tan, Nicholas Y Q %A Tang, Hua %A Taylor, Kent D %A Teo, Yik Ying %A Tham, Yih Chung %A Turner, Stephen T %A Uitterlinden, André G %A Vollenweider, Peter %A Waldenberger, Melanie %A Wang, Lihua %A Wang, Ya Xing %A Wei, Wen Bin %A Williams, Christine %A Yao, Jie %A Yu, Caizheng %A Yuan, Jian-Min %A Zhao, Wei %A Zonderman, Alan B %A Becker, Diane M %A Boehnke, Michael %A Bowden, Donald W %A Chambers, John C %A Deary, Ian J %A Esko, Tõnu %A Farrall, Martin %A Franks, Paul W %A Freedman, Barry I %A Froguel, Philippe %A Gasparini, Paolo %A Gieger, Christian %A Jonas, Jost Bruno %A Kamatani, Yoichiro %A Kato, Norihiro %A Kooner, Jaspal S %A Kutalik, Zoltán %A Laakso, Markku %A Laurie, Cathy C %A Leander, Karin %A Lehtimäki, Terho %A Study, Lifelines Cohort %A Magnusson, Patrik K E %A Oldehinkel, Albertine J %A Penninx, Brenda W J H %A Polasek, Ozren %A Porteous, David J %A Rauramaa, Rainer %A Samani, Nilesh J %A Scott, James %A Shu, Xiao-Ou %A van der Harst, Pim %A Wagenknecht, Lynne E %A Wareham, Nicholas J %A Watkins, Hugh %A Weir, David R %A Wickremasinghe, Ananda R %A Wu, Tangchun %A Zheng, Wei %A Bouchard, Claude %A Christensen, Kaare %A Evans, Michele K %A Gudnason, Vilmundur %A Horta, Bernardo L %A Kardia, Sharon L R %A Liu, Yongmei %A Pereira, Alexandre C %A Psaty, Bruce M %A Ridker, Paul M %A van Dam, Rob M %A Gauderman, W James %A Zhu, Xiaofeng %A Mook-Kanamori, Dennis O %A Fornage, Myriam %A Rotimi, Charles N %A Cupples, L Adrienne %A Kelly, Tanika N %A Fox, Ervin R %A Hayward, Caroline %A van Duijn, Cornelia M %A Tai, E Shyong %A Wong, Tien Yin %A Kooperberg, Charles %A Palmas, Walter %A Rice, Kenneth %A Morrison, Alanna C %A Elliott, Paul %A Caulfield, Mark J %A Munroe, Patricia B %A Rao, Dabeeru C %A Province, Michael A %A Levy, Daniel %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Alcohol Drinking %K Blood Pressure %K Cohort Studies %K Continental Population Groups %K Female %K Gene-Environment Interaction %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Hypertension %K Male %K Middle Aged %K Pedigree %K Polymorphism, Single Nucleotide %K Young Adult %X

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.

%B PLoS One %V 13 %P e0198166 %8 2018 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/29912962?dopt=Abstract %R 10.1371/journal.pone.0198166 %0 Journal Article %J Nat Genet %D 2017 %T Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. %A Day, Felix R %A Thompson, Deborah J %A Helgason, Hannes %A Chasman, Daniel I %A Finucane, Hilary %A Sulem, Patrick %A Ruth, Katherine S %A Whalen, Sean %A Sarkar, Abhishek K %A Albrecht, Eva %A Altmaier, Elisabeth %A Amini, Marzyeh %A Barbieri, Caterina M %A Boutin, Thibaud %A Campbell, Archie %A Demerath, Ellen %A Giri, Ayush %A He, Chunyan %A Hottenga, Jouke J %A Karlsson, Robert %A Kolcic, Ivana %A Loh, Po-Ru %A Lunetta, Kathryn L %A Mangino, Massimo %A Marco, Brumat %A McMahon, George %A Medland, Sarah E %A Nolte, Ilja M %A Noordam, Raymond %A Nutile, Teresa %A Paternoster, Lavinia %A Perjakova, Natalia %A Porcu, Eleonora %A Rose, Lynda M %A Schraut, Katharina E %A Segrè, Ayellet V %A Smith, Albert V %A Stolk, Lisette %A Teumer, Alexander %A Andrulis, Irene L %A Bandinelli, Stefania %A Beckmann, Matthias W %A Benitez, Javier %A Bergmann, Sven %A Bochud, Murielle %A Boerwinkle, Eric %A Bojesen, Stig E %A Bolla, Manjeet K %A Brand, Judith S %A Brauch, Hiltrud %A Brenner, Hermann %A Broer, Linda %A Brüning, Thomas %A Buring, Julie E %A Campbell, Harry %A Catamo, Eulalia %A Chanock, Stephen %A Chenevix-Trench, Georgia %A Corre, Tanguy %A Couch, Fergus J %A Cousminer, Diana L %A Cox, Angela %A Crisponi, Laura %A Czene, Kamila %A Davey Smith, George %A de Geus, Eco J C N %A de Mutsert, Renée %A De Vivo, Immaculata %A Dennis, Joe %A Devilee, Peter %A Dos-Santos-Silva, Isabel %A Dunning, Alison M %A Eriksson, Johan G %A Fasching, Peter A %A Fernández-Rhodes, Lindsay %A Ferrucci, Luigi %A Flesch-Janys, Dieter %A Franke, Lude %A Gabrielson, Marike %A Gandin, Ilaria %A Giles, Graham G %A Grallert, Harald %A Gudbjartsson, Daniel F %A Guenel, Pascal %A Hall, Per %A Hallberg, Emily %A Hamann, Ute %A Harris, Tamara B %A Hartman, Catharina A %A Heiss, Gerardo %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank %A Hunter, David J %A Ikram, M Arfan %A Im, Hae Kyung %A Järvelin, Marjo-Riitta %A Joshi, Peter K %A Karasik, David %A Kellis, Manolis %A Kutalik, Zoltán %A LaChance, Genevieve %A Lambrechts, Diether %A Langenberg, Claudia %A Launer, Lenore J %A Laven, Joop S E %A Lenarduzzi, Stefania %A Li, Jingmei %A Lind, Penelope A %A Lindström, Sara %A Liu, Yongmei %A Luan, Jian'an %A Mägi, Reedik %A Mannermaa, Arto %A Mbarek, Hamdi %A McCarthy, Mark I %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Metspalu, Andres %A Michailidou, Kyriaki %A Milani, Lili %A Milne, Roger L %A Montgomery, Grant W %A Mulligan, Anna M %A Nalls, Mike A %A Navarro, Pau %A Nevanlinna, Heli %A Nyholt, Dale R %A Oldehinkel, Albertine J %A O'Mara, Tracy A %A Padmanabhan, Sandosh %A Palotie, Aarno %A Pedersen, Nancy %A Peters, Annette %A Peto, Julian %A Pharoah, Paul D P %A Pouta, Anneli %A Radice, Paolo %A Rahman, Iffat %A Ring, Susan M %A Robino, Antonietta %A Rosendaal, Frits R %A Rudan, Igor %A Rueedi, Rico %A Ruggiero, Daniela %A Sala, Cinzia F %A Schmidt, Marjanka K %A Scott, Robert A %A Shah, Mitul %A Sorice, Rossella %A Southey, Melissa C %A Sovio, Ulla %A Stampfer, Meir %A Steri, Maristella %A Strauch, Konstantin %A Tanaka, Toshiko %A Tikkanen, Emmi %A Timpson, Nicholas J %A Traglia, Michela %A Truong, Therese %A Tyrer, Jonathan P %A Uitterlinden, André G %A Edwards, Digna R Velez %A Vitart, Veronique %A Völker, Uwe %A Vollenweider, Peter %A Wang, Qin %A Widen, Elisabeth %A van Dijk, Ko Willems %A Willemsen, Gonneke %A Winqvist, Robert %A Wolffenbuttel, Bruce H R %A Zhao, Jing Hua %A Zoledziewska, Magdalena %A Zygmunt, Marek %A Alizadeh, Behrooz Z %A Boomsma, Dorret I %A Ciullo, Marina %A Cucca, Francesco %A Esko, Tõnu %A Franceschini, Nora %A Gieger, Christian %A Gudnason, Vilmundur %A Hayward, Caroline %A Kraft, Peter %A Lawlor, Debbie A %A Magnusson, Patrik K E %A Martin, Nicholas G %A Mook-Kanamori, Dennis O %A Nohr, Ellen A %A Polasek, Ozren %A Porteous, David %A Price, Alkes L %A Ridker, Paul M %A Snieder, Harold %A Spector, Tim D %A Stöckl, Doris %A Toniolo, Daniela %A Ulivi, Sheila %A Visser, Jenny A %A Völzke, Henry %A Wareham, Nicholas J %A Wilson, James F %A Spurdle, Amanda B %A Thorsteindottir, Unnur %A Pollard, Katherine S %A Easton, Douglas F %A Tung, Joyce Y %A Chang-Claude, Jenny %A Hinds, David %A Murray, Anna %A Murabito, Joanne M %A Stefansson, Kari %A Ong, Ken K %A Perry, John R B %K Adolescent %K Age Factors %K Body Mass Index %K Databases, Genetic %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomic Imprinting %K Humans %K Intercellular Signaling Peptides and Proteins %K Male %K Membrane Proteins %K Menarche %K Neoplasms %K Polymorphism, Single Nucleotide %K Puberty %K Quantitative Trait Loci %K Ribonucleoproteins %K Risk Factors %X

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.

%B Nat Genet %V 49 %P 834-841 %8 2017 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/28436984?dopt=Abstract %R 10.1038/ng.3841 %0 Journal Article %J Hypertension %D 2017 %T Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. %A Wain, Louise V %A Vaez, Ahmad %A Jansen, Rick %A Joehanes, Roby %A van der Most, Peter J %A Erzurumluoglu, A Mesut %A O'Reilly, Paul F %A Cabrera, Claudia P %A Warren, Helen R %A Rose, Lynda M %A Verwoert, Germaine C %A Hottenga, Jouke-Jan %A Strawbridge, Rona J %A Esko, Tõnu %A Arking, Dan E %A Hwang, Shih-Jen %A Guo, Xiuqing %A Kutalik, Zoltán %A Trompet, Stella %A Shrine, Nick %A Teumer, Alexander %A Ried, Janina S %A Bis, Joshua C %A Smith, Albert V %A Amin, Najaf %A Nolte, Ilja M %A Lyytikäinen, Leo-Pekka %A Mahajan, Anubha %A Wareham, Nicholas J %A Hofer, Edith %A Joshi, Peter K %A Kristiansson, Kati %A Traglia, Michela %A Havulinna, Aki S %A Goel, Anuj %A Nalls, Mike A %A Sõber, Siim %A Vuckovic, Dragana %A Luan, Jian'an %A del Greco M, Fabiola %A Ayers, Kristin L %A Marrugat, Jaume %A Ruggiero, Daniela %A Lopez, Lorna M %A Niiranen, Teemu %A Enroth, Stefan %A Jackson, Anne U %A Nelson, Christopher P %A Huffman, Jennifer E %A Zhang, Weihua %A Marten, Jonathan %A Gandin, Ilaria %A Harris, Sarah E %A Zemunik, Tatijana %A Lu, Yingchang %A Evangelou, Evangelos %A Shah, Nabi %A de Borst, Martin H %A Mangino, Massimo %A Prins, Bram P %A Campbell, Archie %A Li-Gao, Ruifang %A Chauhan, Ganesh %A Oldmeadow, Christopher %A Abecasis, Goncalo %A Abedi, Maryam %A Barbieri, Caterina M %A Barnes, Michael R %A Batini, Chiara %A Beilby, John %A Blake, Tineka %A Boehnke, Michael %A Bottinger, Erwin P %A Braund, Peter S %A Brown, Morris %A Brumat, Marco %A Campbell, Harry %A Chambers, John C %A Cocca, Massimiliano %A Collins, Francis %A Connell, John %A Cordell, Heather J %A Damman, Jeffrey J %A Davies, Gail %A de Geus, Eco J %A de Mutsert, Renée %A Deelen, Joris %A Demirkale, Yusuf %A Doney, Alex S F %A Dörr, Marcus %A Farrall, Martin %A Ferreira, Teresa %A Frånberg, Mattias %A Gao, He %A Giedraitis, Vilmantas %A Gieger, Christian %A Giulianini, Franco %A Gow, Alan J %A Hamsten, Anders %A Harris, Tamara B %A Hofman, Albert %A Holliday, Elizabeth G %A Hui, Jennie %A Järvelin, Marjo-Riitta %A Johansson, Åsa %A Johnson, Andrew D %A Jousilahti, Pekka %A Jula, Antti %A Kähönen, Mika %A Kathiresan, Sekar %A Khaw, Kay-Tee %A Kolcic, Ivana %A Koskinen, Seppo %A Langenberg, Claudia %A Larson, Marty %A Launer, Lenore J %A Lehne, Benjamin %A Liewald, David C M %A Lin, Li %A Lind, Lars %A Mach, François %A Mamasoula, Chrysovalanto %A Menni, Cristina %A Mifsud, Borbala %A Milaneschi, Yuri %A Morgan, Anna %A Morris, Andrew D %A Morrison, Alanna C %A Munson, Peter J %A Nandakumar, Priyanka %A Nguyen, Quang Tri %A Nutile, Teresa %A Oldehinkel, Albertine J %A Oostra, Ben A %A Org, Elin %A Padmanabhan, Sandosh %A Palotie, Aarno %A Paré, Guillaume %A Pattie, Alison %A Penninx, Brenda W J H %A Poulter, Neil %A Pramstaller, Peter P %A Raitakari, Olli T %A Ren, Meixia %A Rice, Kenneth %A Ridker, Paul M %A Riese, Harriëtte %A Ripatti, Samuli %A Robino, Antonietta %A Rotter, Jerome I %A Rudan, Igor %A Saba, Yasaman %A Saint Pierre, Aude %A Sala, Cinzia F %A Sarin, Antti-Pekka %A Schmidt, Reinhold %A Scott, Rodney %A Seelen, Marc A %A Shields, Denis C %A Siscovick, David %A Sorice, Rossella %A Stanton, Alice %A Stott, David J %A Sundström, Johan %A Swertz, Morris %A Taylor, Kent D %A Thom, Simon %A Tzoulaki, Ioanna %A Tzourio, Christophe %A Uitterlinden, André G %A Völker, Uwe %A Vollenweider, Peter %A Wild, Sarah %A Willemsen, Gonneke %A Wright, Alan F %A Yao, Jie %A Thériault, Sébastien %A Conen, David %A Attia, John %A Sever, Peter %A Debette, Stéphanie %A Mook-Kanamori, Dennis O %A Zeggini, Eleftheria %A Spector, Tim D %A van der Harst, Pim %A Palmer, Colin N A %A Vergnaud, Anne-Claire %A Loos, Ruth J F %A Polasek, Ozren %A Starr, John M %A Girotto, Giorgia %A Hayward, Caroline %A Kooner, Jaspal S %A Lindgren, Cecila M %A Vitart, Veronique %A Samani, Nilesh J %A Tuomilehto, Jaakko %A Gyllensten, Ulf %A Knekt, Paul %A Deary, Ian J %A Ciullo, Marina %A Elosua, Roberto %A Keavney, Bernard D %A Hicks, Andrew A %A Scott, Robert A %A Gasparini, Paolo %A Laan, Maris %A Liu, Yongmei %A Watkins, Hugh %A Hartman, Catharina A %A Salomaa, Veikko %A Toniolo, Daniela %A Perola, Markus %A Wilson, James F %A Schmidt, Helena %A Zhao, Jing Hua %A Lehtimäki, Terho %A van Duijn, Cornelia M %A Gudnason, Vilmundur %A Psaty, Bruce M %A Peters, Annette %A Rettig, Rainer %A James, Alan %A Jukema, J Wouter %A Strachan, David P %A Palmas, Walter %A Metspalu, Andres %A Ingelsson, Erik %A Boomsma, Dorret I %A Franco, Oscar H %A Bochud, Murielle %A Newton-Cheh, Christopher %A Munroe, Patricia B %A Elliott, Paul %A Chasman, Daniel I %A Chakravarti, Aravinda %A Knight, Joanne %A Morris, Andrew P %A Levy, Daniel %A Tobin, Martin D %A Snieder, Harold %A Caulfield, Mark J %A Ehret, Georg B %X

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.

%B Hypertension %8 2017 Jul 24 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28739976?dopt=Abstract %R 10.1161/HYPERTENSIONAHA.117.09438 %0 Journal Article %J Nature %D 2017 %T Rare and low-frequency coding variants alter human adult height. %A Marouli, Eirini %A Graff, Mariaelisa %A Medina-Gomez, Carolina %A Lo, Ken Sin %A Wood, Andrew R %A Kjaer, Troels R %A Fine, Rebecca S %A Lu, Yingchang %A Schurmann, Claudia %A Highland, Heather M %A Rüeger, Sina %A Thorleifsson, Gudmar %A Justice, Anne E %A Lamparter, David %A Stirrups, Kathleen E %A Turcot, Valérie %A Young, Kristin L %A Winkler, Thomas W %A Esko, Tõnu %A Karaderi, Tugce %A Locke, Adam E %A Masca, Nicholas G D %A Ng, Maggie C Y %A Mudgal, Poorva %A Rivas, Manuel A %A Vedantam, Sailaja %A Mahajan, Anubha %A Guo, Xiuqing %A Abecasis, Goncalo %A Aben, Katja K %A Adair, Linda S %A Alam, Dewan S %A Albrecht, Eva %A Allin, Kristine H %A Allison, Matthew %A Amouyel, Philippe %A Appel, Emil V %A Arveiler, Dominique %A Asselbergs, Folkert W %A Auer, Paul L %A Balkau, Beverley %A Banas, Bernhard %A Bang, Lia E %A Benn, Marianne %A Bergmann, Sven %A Bielak, Lawrence F %A Blüher, Matthias %A Boeing, Heiner %A Boerwinkle, Eric %A Böger, Carsten A %A Bonnycastle, Lori L %A Bork-Jensen, Jette %A Bots, Michiel L %A Bottinger, Erwin P %A Bowden, Donald W %A Brandslund, Ivan %A Breen, Gerome %A Brilliant, Murray H %A Broer, Linda %A Burt, Amber A %A Butterworth, Adam S %A Carey, David J %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Cocca, Massimiliano %A Collins, Francis S %A Cook, James P %A Corley, Janie %A Galbany, Jordi Corominas %A Cox, Amanda J %A Cuellar-Partida, Gabriel %A Danesh, John %A Davies, Gail %A de Bakker, Paul I W %A de Borst, Gert J %A de Denus, Simon %A de Groot, Mark C H %A de Mutsert, Renée %A Deary, Ian J %A Dedoussis, George %A Demerath, Ellen W %A den Hollander, Anneke I %A Dennis, Joe G %A Di Angelantonio, Emanuele %A Drenos, Fotios %A Du, Mengmeng %A Dunning, Alison M %A Easton, Douglas F %A Ebeling, Tapani %A Edwards, Todd L %A Ellinor, Patrick T %A Elliott, Paul %A Evangelou, Evangelos %A Farmaki, Aliki-Eleni %A Faul, Jessica D %A Feitosa, Mary F %A Feng, Shuang %A Ferrannini, Ele %A Ferrario, Marco M %A Ferrières, Jean %A Florez, Jose C %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frikke-Schmidt, Ruth %A Galesloot, Tessel E %A Gan, Wei %A Gandin, Ilaria %A Gasparini, Paolo %A Giedraitis, Vilmantas %A Giri, Ayush %A Girotto, Giorgia %A Gordon, Scott D %A Gordon-Larsen, Penny %A Gorski, Mathias %A Grarup, Niels %A Grove, Megan L %A Gudnason, Vilmundur %A Gustafsson, Stefan %A Hansen, Torben %A Harris, Kathleen Mullan %A Harris, Tamara B %A Hattersley, Andrew T %A Hayward, Caroline %A He, Liang %A Heid, Iris M %A Heikkilä, Kauko %A Helgeland, Øyvind %A Hernesniemi, Jussi %A Hewitt, Alex W %A Hocking, Lynne J %A Hollensted, Mette %A Holmen, Oddgeir L %A Hovingh, G Kees %A Howson, Joanna M M %A Hoyng, Carel B %A Huang, Paul L %A Hveem, Kristian %A Ikram, M Arfan %A Ingelsson, Erik %A Jackson, Anne U %A Jansson, Jan-Håkan %A Jarvik, Gail P %A Jensen, Gorm B %A Jhun, Min A %A Jia, Yucheng %A Jiang, Xuejuan %A Johansson, Stefan %A Jørgensen, Marit E %A Jørgensen, Torben %A Jousilahti, Pekka %A Jukema, J Wouter %A Kahali, Bratati %A Kahn, René S %A Kähönen, Mika %A Kamstrup, Pia R %A Kanoni, Stavroula %A Kaprio, Jaakko %A Karaleftheri, Maria %A Kardia, Sharon L R %A Karpe, Fredrik %A Kee, Frank %A Keeman, Renske %A Kiemeney, Lambertus A %A Kitajima, Hidetoshi %A Kluivers, Kirsten B %A Kocher, Thomas %A Komulainen, Pirjo %A Kontto, Jukka %A Kooner, Jaspal S %A Kooperberg, Charles %A Kovacs, Peter %A Kriebel, Jennifer %A Kuivaniemi, Helena %A Küry, Sébastien %A Kuusisto, Johanna %A La Bianca, Martina %A Laakso, Markku %A Lakka, Timo A %A Lange, Ethan M %A Lange, Leslie A %A Langefeld, Carl D %A Langenberg, Claudia %A Larson, Eric B %A Lee, I-Te %A Lehtimäki, Terho %A Lewis, Cora E %A Li, Huaixing %A Li, Jin %A Li-Gao, Ruifang %A Lin, Honghuang %A Lin, Li-An %A Lin, Xu %A Lind, Lars %A Lindström, Jaana %A Linneberg, Allan %A Liu, Yeheng %A Liu, Yongmei %A Lophatananon, Artitaya %A Luan, Jian'an %A Lubitz, Steven A %A Lyytikäinen, Leo-Pekka %A Mackey, David A %A Madden, Pamela A F %A Manning, Alisa K %A Männistö, Satu %A Marenne, Gaëlle %A Marten, Jonathan %A Martin, Nicholas G %A Mazul, Angela L %A Meidtner, Karina %A Metspalu, Andres %A Mitchell, Paul %A Mohlke, Karen L %A Mook-Kanamori, Dennis O %A Morgan, Anna %A Morris, Andrew D %A Morris, Andrew P %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Nalls, Mike A %A Nauck, Matthias %A Nelson, Christopher P %A Neville, Matt %A Nielsen, Sune F %A Nikus, Kjell %A Njølstad, Pål R %A Nordestgaard, Børge G %A Ntalla, Ioanna %A O'Connel, Jeffrey R %A Oksa, Heikki %A Loohuis, Loes M Olde %A Ophoff, Roel A %A Owen, Katharine R %A Packard, Chris J %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasterkamp, Gerard %A Patel, Aniruddh P %A Pattie, Alison %A Pedersen, Oluf %A Peissig, Peggy L %A Peloso, Gina M %A Pennell, Craig E %A Perola, Markus %A Perry, James A %A Perry, John R B %A Person, Thomas N %A Pirie, Ailith %A Polasek, Ozren %A Posthuma, Danielle %A Raitakari, Olli T %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil %A Robino, Antonietta %A Rolandsson, Olov %A Rudan, Igor %A Ruth, Katherine S %A Saleheen, Danish %A Salomaa, Veikko %A Samani, Nilesh J %A Sandow, Kevin %A Sapkota, Yadav %A Sattar, Naveed %A Schmidt, Marjanka K %A Schreiner, Pamela J %A Schulze, Matthias B %A Scott, Robert A %A Segura-Lepe, Marcelo P %A Shah, Svati %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert Vernon %A Smith, Jennifer A %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Steinthorsdottir, Valgerdur %A Stringham, Heather M %A Stumvoll, Michael %A Surendran, Praveen %A 't Hart, Leen M %A Tansey, Katherine E %A Tardif, Jean-Claude %A Taylor, Kent D %A Teumer, Alexander %A Thompson, Deborah J %A Thorsteinsdottir, Unnur %A Thuesen, Betina H %A Tönjes, Anke %A Tromp, Gerard %A Trompet, Stella %A Tsafantakis, Emmanouil %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A Tyrer, Jonathan P %A Uher, Rudolf %A Uitterlinden, André G %A Ulivi, Sheila %A van der Laan, Sander W %A Van Der Leij, Andries R %A van Duijn, Cornelia M %A van Schoor, Natasja M %A van Setten, Jessica %A Varbo, Anette %A Varga, Tibor V %A Varma, Rohit %A Edwards, Digna R Velez %A Vermeulen, Sita H %A Vestergaard, Henrik %A Vitart, Veronique %A Vogt, Thomas F %A Vozzi, Diego %A Walker, Mark %A Wang, Feijie %A Wang, Carol A %A Wang, Shuai %A Wang, Yiqin %A Wareham, Nicholas J %A Warren, Helen R %A Wessel, Jennifer %A Willems, Sara M %A Wilson, James G %A Witte, Daniel R %A Woods, Michael O %A Wu, Ying %A Yaghootkar, Hanieh %A Yao, Jie %A Yao, Pang %A Yerges-Armstrong, Laura M %A Young, Robin %A Zeggini, Eleftheria %A Zhan, Xiaowei %A Zhang, Weihua %A Zhao, Jing Hua %A Zhao, Wei %A Zhao, Wei %A Zheng, He %A Zhou, Wei %A Rotter, Jerome I %A Boehnke, Michael %A Kathiresan, Sekar %A McCarthy, Mark I %A Willer, Cristen J %A Stefansson, Kari %A Borecki, Ingrid B %A Liu, Dajiang J %A North, Kari E %A Heard-Costa, Nancy L %A Pers, Tune H %A Lindgren, Cecilia M %A Oxvig, Claus %A Kutalik, Zoltán %A Rivadeneira, Fernando %A Loos, Ruth J F %A Frayling, Timothy M %A Hirschhorn, Joel N %A Deloukas, Panos %A Lettre, Guillaume %K ADAMTS Proteins %K Adult %K Alleles %K Body Height %K Cell Adhesion Molecules %K Female %K Gene Frequency %K Genetic Variation %K Genome, Human %K Glycoproteins %K Glycosaminoglycans %K Hedgehog Proteins %K Humans %K Intercellular Signaling Peptides and Proteins %K Interferon Regulatory Factors %K Interleukin-11 Receptor alpha Subunit %K Male %K Multifactorial Inheritance %K NADPH Oxidase 4 %K NADPH Oxidases %K Phenotype %K Pregnancy-Associated Plasma Protein-A %K Procollagen N-Endopeptidase %K Proteoglycans %K Proteolysis %K Receptors, Androgen %K Somatomedins %X

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.

%B Nature %V 542 %P 186-190 %8 2017 02 09 %G eng %N 7640 %1 http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract %R 10.1038/nature21039 %0 Journal Article %J Mutat Res %D 2017 %T Targeted sequencing identifies novel variants involved in autosomal recessive hereditary hearing loss in Qatari families. %A Alkowari, Moza K %A Vozzi, Diego %A Bhagat, Shruti %A Krishnamoorthy, Navaneethakrishnan %A Morgan, Anna %A Hayder, Yousra %A Logendra, Barathy %A Najjar, Nehal %A Gandin, Ilaria %A Gasparini, Paolo %A Badii, Ramin %A Girotto, Giorgia %A Abdulhadi, Khalid %K Adolescent %K Alleles %K Cadherins %K Child %K Child, Preschool %K Connexins %K Female %K GPI-Linked Proteins %K Hearing Loss, Sensorineural %K Humans %K Infant %K Male %K Membrane Proteins %K Models, Molecular %K Mutation %K Myosin Heavy Chains %K Pedigree %K Protein Conformation %K Qatar %K Sequence Analysis, DNA %X

Hereditary hearing loss is characterized by a very high genetic heterogeneity. In the Qatari population the role of GJB2, the worldwide HHL major player, seems to be quite limited compared to Caucasian populations. In this study we analysed 18 Qatari families affected by non-syndromic hearing loss using a targeted sequencing approach that allowed us to analyse 81 genes simultaneously. Thanks to this approach, 50% of these families (9 out of 18) resulted positive for the presence of likely causative alleles in 6 different genes: CDH23, MYO6, GJB6, OTOF, TMC1 and OTOA. In particular, 4 novel alleles were detected while the remaining ones were already described to be associated to HHL in other ethnic groups. Molecular modelling has been used to further investigate the role of novel alleles identified in CDH23 and TMC1 genes demonstrating their crucial role in Ca2+ binding and therefore possible functional role in proteins. Present study showed that an accurate molecular diagnosis based on next generation sequencing technologies might largely improve molecular diagnostics outcome leading to benefits for both genetic counseling and definition of recurrence risk.

%B Mutat Res %V 800-802 %P 29-36 %8 2017 08 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/28501645?dopt=Abstract %R 10.1016/j.mrfmmm.2017.05.001 %0 Journal Article %J Nature %D 2016 %T Genome-wide association study identifies 74 loci associated with educational attainment. %A Okbay, Aysu %A Beauchamp, Jonathan P %A Fontana, Mark Alan %A Lee, James J %A Pers, Tune H %A Rietveld, Cornelius A %A Turley, Patrick %A Chen, Guo-Bo %A Emilsson, Valur %A Meddens, S Fleur W %A Oskarsson, Sven %A Pickrell, Joseph K %A Thom, Kevin %A Timshel, Pascal %A de Vlaming, Ronald %A Abdellaoui, Abdel %A Ahluwalia, Tarunveer S %A Bacelis, Jonas %A Baumbach, Clemens %A Bjornsdottir, Gyda %A Brandsma, Johannes H %A Pina Concas, Maria %A Derringer, Jaime %A Furlotte, Nicholas A %A Galesloot, Tessel E %A Girotto, Giorgia %A Gupta, Richa %A Hall, Leanne M %A Harris, Sarah E %A Hofer, Edith %A Horikoshi, Momoko %A Huffman, Jennifer E %A Kaasik, Kadri %A Kalafati, Ioanna P %A Karlsson, Robert %A Kong, Augustine %A Lahti, Jari %A van der Lee, Sven J %A deLeeuw, Christiaan %A Lind, Penelope A %A Lindgren, Karl-Oskar %A Liu, Tian %A Mangino, Massimo %A Marten, Jonathan %A Mihailov, Evelin %A Miller, Michael B %A van der Most, Peter J %A Oldmeadow, Christopher %A Payton, Antony %A Pervjakova, Natalia %A Peyrot, Wouter J %A Qian, Yong %A Raitakari, Olli %A Rueedi, Rico %A Salvi, Erika %A Schmidt, Börge %A Schraut, Katharina E %A Shi, Jianxin %A Smith, Albert V %A Poot, Raymond A %A St Pourcain, Beate %A Teumer, Alexander %A Thorleifsson, Gudmar %A Verweij, Niek %A Vuckovic, Dragana %A Wellmann, Juergen %A Westra, Harm-Jan %A Yang, Jingyun %A Zhao, Wei %A Zhu, Zhihong %A Alizadeh, Behrooz Z %A Amin, Najaf %A Bakshi, Andrew %A Baumeister, Sebastian E %A Biino, Ginevra %A Bønnelykke, Klaus %A Boyle, Patricia A %A Campbell, Harry %A Cappuccio, Francesco P %A Davies, Gail %A De Neve, Jan-Emmanuel %A Deloukas, Panos %A Demuth, Ilja %A Ding, Jun %A Eibich, Peter %A Eisele, Lewin %A Eklund, Niina %A Evans, David M %A Faul, Jessica D %A Feitosa, Mary F %A Forstner, Andreas J %A Gandin, Ilaria %A Gunnarsson, Bjarni %A Halldórsson, Bjarni V %A Harris, Tamara B %A Heath, Andrew C %A Hocking, Lynne J %A Holliday, Elizabeth G %A Homuth, Georg %A Horan, Michael A %A Hottenga, Jouke-Jan %A de Jager, Philip L %A Joshi, Peter K %A Jugessur, Astanand %A Kaakinen, Marika A %A Kähönen, Mika %A Kanoni, Stavroula %A Keltigangas-Järvinen, Liisa %A Kiemeney, Lambertus A L M %A Kolcic, Ivana %A Koskinen, Seppo %A Kraja, Aldi T %A Kroh, Martin %A Kutalik, Zoltán %A Latvala, Antti %A Launer, Lenore J %A Lebreton, Maël P %A Levinson, Douglas F %A Lichtenstein, Paul %A Lichtner, Peter %A Liewald, David C M %A Loukola, Anu %A Madden, Pamela A %A Mägi, Reedik %A Mäki-Opas, Tomi %A Marioni, Riccardo E %A Marques-Vidal, Pedro %A Meddens, Gerardus A %A McMahon, George %A Meisinger, Christa %A Meitinger, Thomas %A Milaneschi, Yusplitri %A Milani, Lili %A Montgomery, Grant W %A Myhre, Ronny %A Nelson, Christopher P %A Nyholt, Dale R %A Ollier, William E R %A Palotie, Aarno %A Paternoster, Lavinia %A Pedersen, Nancy L %A Petrovic, Katja E %A Porteous, David J %A Räikkönen, Katri %A Ring, Susan M %A Robino, Antonietta %A Rostapshova, Olga %A Rudan, Igor %A Rustichini, Aldo %A Salomaa, Veikko %A Sanders, Alan R %A Sarin, Antti-Pekka %A Schmidt, Helena %A Scott, Rodney J %A Smith, Blair H %A Smith, Jennifer A %A Staessen, Jan A %A Steinhagen-Thiessen, Elisabeth %A Strauch, Konstantin %A Terracciano, Antonio %A Tobin, Martin D %A Ulivi, Sheila %A Vaccargiu, Simona %A Quaye, Lydia %A van Rooij, Frank J A %A Venturini, Cristina %A Vinkhuyzen, Anna A E %A Völker, Uwe %A Völzke, Henry %A Vonk, Judith M %A Vozzi, Diego %A Waage, Johannes %A Ware, Erin B %A Willemsen, Gonneke %A Attia, John R %A Bennett, David A %A Berger, Klaus %A Bertram, Lars %A Bisgaard, Hans %A Boomsma, Dorret I %A Borecki, Ingrid B %A Bültmann, Ute %A Chabris, Christopher F %A Cucca, Francesco %A Cusi, Daniele %A Deary, Ian J %A Dedoussis, George V %A van Duijn, Cornelia M %A Eriksson, Johan G %A Franke, Barbara %A Franke, Lude %A Gasparini, Paolo %A Gejman, Pablo V %A Gieger, Christian %A Grabe, Hans-Jörgen %A Gratten, Jacob %A Groenen, Patrick J F %A Gudnason, Vilmundur %A van der Harst, Pim %A Hayward, Caroline %A Hinds, David A %A Hoffmann, Wolfgang %A Hyppönen, Elina %A Iacono, William G %A Jacobsson, Bo %A Järvelin, Marjo-Riitta %A Jöckel, Karl-Heinz %A Kaprio, Jaakko %A Kardia, Sharon L R %A Lehtimäki, Terho %A Lehrer, Steven F %A Magnusson, Patrik K E %A Martin, Nicholas G %A McGue, Matt %A Metspalu, Andres %A Pendleton, Neil %A Penninx, Brenda W J H %A Perola, Markus %A Pirastu, Nicola %A Pirastu, Mario %A Polasek, Ozren %A Posthuma, Danielle %A Power, Christine %A Province, Michael A %A Samani, Nilesh J %A Schlessinger, David %A Schmidt, Reinhold %A Sørensen, Thorkild I A %A Spector, Tim D %A Stefansson, Kari %A Thorsteinsdottir, Unnur %A Thurik, A Roy %A Timpson, Nicholas J %A Tiemeier, Henning %A Tung, Joyce Y %A Uitterlinden, André G %A Vitart, Veronique %A Vollenweider, Peter %A Weir, David R %A Wilson, James F %A Wright, Alan F %A Conley, Dalton C %A Krueger, Robert F %A Davey Smith, George %A Hofman, Albert %A Laibson, David I %A Medland, Sarah E %A Meyer, Michelle N %A Yang, Jian %A Johannesson, Magnus %A Visscher, Peter M %A Esko, Tõnu %A Koellinger, Philipp D %A Cesarini, David %A Benjamin, Daniel J %K Alzheimer Disease %K Bipolar Disorder %K Brain %K Cognition %K Computational Biology %K Educational Status %K Fetus %K Gene Expression Regulation %K Gene-Environment Interaction %K Genome-Wide Association Study %K Great Britain %K Humans %K Molecular Sequence Annotation %K Polymorphism, Single Nucleotide %K Schizophrenia %X

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.

%B Nature %V 533 %P 539-42 %8 2016 May 26 %G eng %N 7604 %1 http://www.ncbi.nlm.nih.gov/pubmed/27225129?dopt=Abstract %R 10.1038/nature17671 %0 Journal Article %J Nat Genet %D 2016 %T A reference panel of 64,976 haplotypes for genotype imputation. %A McCarthy, Shane %A Das, Sayantan %A Kretzschmar, Warren %A Delaneau, Olivier %A Wood, Andrew R %A Teumer, Alexander %A Kang, Hyun Min %A Fuchsberger, Christian %A Danecek, Petr %A Sharp, Kevin %A Luo, Yang %A Sidore, Carlo %A Kwong, Alan %A Timpson, Nicholas %A Koskinen, Seppo %A Vrieze, Scott %A Scott, Laura J %A Zhang, He %A Mahajan, Anubha %A Veldink, Jan %A Peters, Ulrike %A Pato, Carlos %A van Duijn, Cornelia M %A Gillies, Christopher E %A Gandin, Ilaria %A Mezzavilla, Massimo %A Gilly, Arthur %A Cocca, Massimiliano %A Traglia, Michela %A Angius, Andrea %A Barrett, Jeffrey C %A Boomsma, Dorrett %A Branham, Kari %A Breen, Gerome %A Brummett, Chad M %A Busonero, Fabio %A Campbell, Harry %A Chan, Andrew %A Chen, Sai %A Chew, Emily %A Collins, Francis S %A Corbin, Laura J %A Smith, George Davey %A Dedoussis, George %A Dörr, Marcus %A Farmaki, Aliki-Eleni %A Ferrucci, Luigi %A Forer, Lukas %A Fraser, Ross M %A Gabriel, Stacey %A Levy, Shawn %A Groop, Leif %A Harrison, Tabitha %A Hattersley, Andrew %A Holmen, Oddgeir L %A Hveem, Kristian %A Kretzler, Matthias %A Lee, James C %A McGue, Matt %A Meitinger, Thomas %A Melzer, David %A Min, Josine L %A Mohlke, Karen L %A Vincent, John B %A Nauck, Matthias %A Nickerson, Deborah %A Palotie, Aarno %A Pato, Michele %A Pirastu, Nicola %A McInnis, Melvin %A Richards, J Brent %A Sala, Cinzia %A Salomaa, Veikko %A Schlessinger, David %A Schoenherr, Sebastian %A Slagboom, P Eline %A Small, Kerrin %A Spector, Timothy %A Stambolian, Dwight %A Tuke, Marcus %A Tuomilehto, Jaakko %A Van den Berg, Leonard H %A van Rheenen, Wouter %A Völker, Uwe %A Wijmenga, Cisca %A Toniolo, Daniela %A Zeggini, Eleftheria %A Gasparini, Paolo %A Sampson, Matthew G %A Wilson, James F %A Frayling, Timothy %A de Bakker, Paul I W %A Swertz, Morris A %A McCarroll, Steven %A Kooperberg, Charles %A Dekker, Annelot %A Altshuler, David %A Willer, Cristen %A Iacono, William %A Ripatti, Samuli %A Soranzo, Nicole %A Walter, Klaudia %A Swaroop, Anand %A Cucca, Francesco %A Anderson, Carl A %A Myers, Richard M %A Boehnke, Michael %A McCarthy, Mark I %A Durbin, Richard %X

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.

%B Nat Genet %8 2016 Aug 22 %G ENG %1 http://www.ncbi.nlm.nih.gov/pubmed/27548312?dopt=Abstract %R 10.1038/ng.3643 %0 Journal Article %J Nature %D 2015 %T Directional dominance on stature and cognition in diverse human populations. %A Joshi, Peter K %A Esko, Tõnu %A Mattsson, Hannele %A Eklund, Niina %A Gandin, Ilaria %A Nutile, Teresa %A Jackson, Anne U %A Schurmann, Claudia %A Smith, Albert V %A Zhang, Weihua %A Okada, Yukinori %A Stančáková, Alena %A Faul, Jessica D %A Zhao, Wei %A Bartz, Traci M %A Concas, Maria Pina %A Franceschini, Nora %A Enroth, Stefan %A Vitart, Veronique %A Trompet, Stella %A Guo, Xiuqing %A Chasman, Daniel I %A O'Connel, Jeffrey R %A Corre, Tanguy %A Nongmaithem, Suraj S %A Chen, Yuning %A Mangino, Massimo %A Ruggiero, Daniela %A Traglia, Michela %A Farmaki, Aliki-Eleni %A Kacprowski, Tim %A Bjonnes, Andrew %A van der Spek, Ashley %A Wu, Ying %A Giri, Anil K %A Yanek, Lisa R %A Wang, Lihua %A Hofer, Edith %A Rietveld, Cornelius A %A McLeod, Olga %A Cornelis, Marilyn C %A Pattaro, Cristian %A Verweij, Niek %A Baumbach, Clemens %A Abdellaoui, Abdel %A Warren, Helen R %A Vuckovic, Dragana %A Mei, Hao %A Bouchard, Claude %A Perry, John R B %A Cappellani, Stefania %A Mirza, Saira S %A Benton, Miles C %A Broeckel, Ulrich %A Medland, Sarah E %A Lind, Penelope A %A Malerba, Giovanni %A Drong, Alexander %A Yengo, Loic %A Bielak, Lawrence F %A Zhi, Degui %A van der Most, Peter J %A Shriner, Daniel %A Mägi, Reedik %A Hemani, Gibran %A Karaderi, Tugce %A Wang, Zhaoming %A Liu, Tian %A Demuth, Ilja %A Zhao, Jing Hua %A Meng, Weihua %A Lataniotis, Lazaros %A van der Laan, Sander W %A Bradfield, Jonathan P %A Wood, Andrew R %A Bonnefond, Amelie %A Ahluwalia, Tarunveer S %A Hall, Leanne M %A Salvi, Erika %A Yazar, Seyhan %A Carstensen, Lisbeth %A de Haan, Hugoline G %A Abney, Mark %A Afzal, Uzma %A Allison, Matthew A %A Amin, Najaf %A Asselbergs, Folkert W %A Bakker, Stephan J L %A Barr, R Graham %A Baumeister, Sebastian E %A Benjamin, Daniel J %A Bergmann, Sven %A Boerwinkle, Eric %A Bottinger, Erwin P %A Campbell, Archie %A Chakravarti, Aravinda %A Chan, Yingleong %A Chanock, Stephen J %A Chen, Constance %A Chen, Y-D Ida %A Collins, Francis S %A Connell, John %A Correa, Adolfo %A Cupples, L Adrienne %A Smith, George Davey %A Davies, Gail %A Dörr, Marcus %A Ehret, Georg %A Ellis, Stephen B %A Feenstra, Bjarke %A Feitosa, Mary F %A Ford, Ian %A Fox, Caroline S %A Frayling, Timothy M %A Friedrich, Nele %A Geller, Frank %A Scotland, Generation %A Gillham-Nasenya, Irina %A Gottesman, Omri %A Graff, Misa %A Grodstein, Francine %A Gu, Charles %A Haley, Chris %A Hammond, Christopher J %A Harris, Sarah E %A Harris, Tamara B %A Hastie, Nicholas D %A Heard-Costa, Nancy L %A Heikkilä, Kauko %A Hocking, Lynne J %A Homuth, Georg %A Hottenga, Jouke-Jan %A Huang, Jinyan %A Huffman, Jennifer E %A Hysi, Pirro G %A Ikram, M Arfan %A Ingelsson, Erik %A Joensuu, Anni %A Johansson, Åsa %A Jousilahti, Pekka %A Jukema, J Wouter %A Kähönen, Mika %A Kamatani, Yoichiro %A Kanoni, Stavroula %A Kerr, Shona M %A Khan, Nazir M %A Koellinger, Philipp %A Koistinen, Heikki A %A Kooner, Manraj K %A Kubo, Michiaki %A Kuusisto, Johanna %A Lahti, Jari %A Launer, Lenore J %A Lea, Rodney A %A Lehne, Benjamin %A Lehtimäki, Terho %A Liewald, David C M %A Lind, Lars %A Loh, Marie %A Lokki, Marja-Liisa %A London, Stephanie J %A Loomis, Stephanie J %A Loukola, Anu %A Lu, Yingchang %A Lumley, Thomas %A Lundqvist, Annamari %A Männistö, Satu %A Marques-Vidal, Pedro %A Masciullo, Corrado %A Matchan, Angela %A Mathias, Rasika A %A Matsuda, Koichi %A Meigs, James B %A Meisinger, Christa %A Meitinger, Thomas %A Menni, Cristina %A Mentch, Frank D %A Mihailov, Evelin %A Milani, Lili %A Montasser, May E %A Montgomery, Grant W %A Morrison, Alanna %A Myers, Richard H %A Nadukuru, Rajiv %A Navarro, Pau %A Nelis, Mari %A Nieminen, Markku S %A Nolte, Ilja M %A O'Connor, George T %A Ogunniyi, Adesola %A Padmanabhan, Sandosh %A Palmas, Walter R %A Pankow, James S %A Patarcic, Inga %A Pavani, Francesca %A Peyser, Patricia A %A Pietilainen, Kirsi %A Poulter, Neil %A Prokopenko, Inga %A Ralhan, Sarju %A Redmond, Paul %A Rich, Stephen S %A Rissanen, Harri %A Robino, Antonietta %A Rose, Lynda M %A Rose, Richard %A Sala, Cinzia %A Salako, Babatunde %A Salomaa, Veikko %A Sarin, Antti-Pekka %A Saxena, Richa %A Schmidt, Helena %A Scott, Laura J %A Scott, William R %A Sennblad, Bengt %A Seshadri, Sudha %A Sever, Peter %A Shrestha, Smeeta %A Smith, Blair H %A Smith, Jennifer A %A Soranzo, Nicole %A Sotoodehnia, Nona %A Southam, Lorraine %A Stanton, Alice V %A Stathopoulou, Maria G %A Strauch, Konstantin %A Strawbridge, Rona J %A Suderman, Matthew J %A Tandon, Nikhil %A Tang, Sian-Tsun %A Taylor, Kent D %A Tayo, Bamidele O %A Töglhofer, Anna Maria %A Tomaszewski, Maciej %A Tšernikova, Natalia %A Tuomilehto, Jaakko %A Uitterlinden, André G %A Vaidya, Dhananjay %A van Hylckama Vlieg, Astrid %A van Setten, Jessica %A Vasankari, Tuula %A Vedantam, Sailaja %A Vlachopoulou, Efthymia %A Vozzi, Diego %A Vuoksimaa, Eero %A Waldenberger, Melanie %A Ware, Erin B %A Wentworth-Shields, William %A Whitfield, John B %A Wild, Sarah %A Willemsen, Gonneke %A Yajnik, Chittaranjan S %A Yao, Jie %A Zaza, Gianluigi %A Zhu, Xiaofeng %A Salem, Rany M %A Melbye, Mads %A Bisgaard, Hans %A Samani, Nilesh J %A Cusi, Daniele %A Mackey, David A %A Cooper, Richard S %A Froguel, Philippe %A Pasterkamp, Gerard %A Grant, Struan F A %A Hakonarson, Hakon %A Ferrucci, Luigi %A Scott, Robert A %A Morris, Andrew D %A Palmer, Colin N A %A Dedoussis, George %A Deloukas, Panos %A Bertram, Lars %A Lindenberger, Ulman %A Berndt, Sonja I %A Lindgren, Cecilia M %A Timpson, Nicholas J %A Tönjes, Anke %A Munroe, Patricia B %A Sørensen, Thorkild I A %A Rotimi, Charles N %A Arnett, Donna K %A Oldehinkel, Albertine J %A Kardia, Sharon L R %A Balkau, Beverley %A Gambaro, Giovanni %A Morris, Andrew P %A Eriksson, Johan G %A Wright, Margie J %A Martin, Nicholas G %A Hunt, Steven C %A Starr, John M %A Deary, Ian J %A Griffiths, Lyn R %A Tiemeier, Henning %A Pirastu, Nicola %A Kaprio, Jaakko %A Wareham, Nicholas J %A Pérusse, Louis %A Wilson, James G %A Girotto, Giorgia %A Caulfield, Mark J %A Raitakari, Olli %A Boomsma, Dorret I %A Gieger, Christian %A van der Harst, Pim %A Hicks, Andrew A %A Kraft, Peter %A Sinisalo, Juha %A Knekt, Paul %A Johannesson, Magnus %A Magnusson, Patrik K E %A Hamsten, Anders %A Schmidt, Reinhold %A Borecki, Ingrid B %A Vartiainen, Erkki %A Becker, Diane M %A Bharadwaj, Dwaipayan %A Mohlke, Karen L %A Boehnke, Michael %A van Duijn, Cornelia M %A Sanghera, Dharambir K %A Teumer, Alexander %A Zeggini, Eleftheria %A Metspalu, Andres %A Gasparini, Paolo %A Ulivi, Sheila %A Ober, Carole %A Toniolo, Daniela %A Rudan, Igor %A Porteous, David J %A Ciullo, Marina %A Spector, Tim D %A Hayward, Caroline %A Dupuis, Josée %A Loos, Ruth J F %A Wright, Alan F %A Chandak, Giriraj R %A Vollenweider, Peter %A Shuldiner, Alan R %A Ridker, Paul M %A Rotter, Jerome I %A Sattar, Naveed %A Gyllensten, Ulf %A North, Kari E %A Pirastu, Mario %A Psaty, Bruce M %A Weir, David R %A Laakso, Markku %A Gudnason, Vilmundur %A Takahashi, Atsushi %A Chambers, John C %A Kooner, Jaspal S %A Strachan, David P %A Campbell, Harry %A Hirschhorn, Joel N %A Perola, Markus %A Polasek, Ozren %A Wilson, James F %K Biological Evolution %K Blood Pressure %K Body Height %K Cholesterol, LDL %K Cognition %K Cohort Studies %K Educational Status %K Female %K Forced Expiratory Volume %K Genome, Human %K Homozygote %K Humans %K Lung Volume Measurements %K Male %K Phenotype %X

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.

%B Nature %V 523 %P 459-62 %8 2015 Jul 23 %G eng %N 7561 %1 http://www.ncbi.nlm.nih.gov/pubmed/26131930?dopt=Abstract %R 10.1038/nature14618 %0 Journal Article %J Nat Genet %D 2015 %T Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. %A Day, Felix R %A Ruth, Katherine S %A Thompson, Deborah J %A Lunetta, Kathryn L %A Pervjakova, Natalia %A Chasman, Daniel I %A Stolk, Lisette %A Finucane, Hilary K %A Sulem, Patrick %A Bulik-Sullivan, Brendan %A Esko, Tõnu %A Johnson, Andrew D %A Elks, Cathy E %A Franceschini, Nora %A He, Chunyan %A Altmaier, Elisabeth %A Brody, Jennifer A %A Franke, Lude L %A Huffman, Jennifer E %A Keller, Margaux F %A McArdle, Patrick F %A Nutile, Teresa %A Porcu, Eleonora %A Robino, Antonietta %A Rose, Lynda M %A Schick, Ursula M %A Smith, Jennifer A %A Teumer, Alexander %A Traglia, Michela %A Vuckovic, Dragana %A Yao, Jie %A Zhao, Wei %A Albrecht, Eva %A Amin, Najaf %A Corre, Tanguy %A Hottenga, Jouke-Jan %A Mangino, Massimo %A Smith, Albert V %A Tanaka, Toshiko %A Abecasis, Goncalo R %A Andrulis, Irene L %A Anton-Culver, Hoda %A Antoniou, Antonis C %A Arndt, Volker %A Arnold, Alice M %A Barbieri, Caterina %A Beckmann, Matthias W %A Beeghly-Fadiel, Alicia %A Benitez, Javier %A Bernstein, Leslie %A Bielinski, Suzette J %A Blomqvist, Carl %A Boerwinkle, Eric %A Bogdanova, Natalia V %A Bojesen, Stig E %A Bolla, Manjeet K %A Borresen-Dale, Anne-Lise %A Boutin, Thibaud S %A Brauch, Hiltrud %A Brenner, Hermann %A Brüning, Thomas %A Burwinkel, Barbara %A Campbell, Archie %A Campbell, Harry %A Chanock, Stephen J %A Chapman, J Ross %A Chen, Yii-Der Ida %A Chenevix-Trench, Georgia %A Couch, Fergus J %A Coviello, Andrea D %A Cox, Angela %A Czene, Kamila %A Darabi, Hatef %A De Vivo, Immaculata %A Demerath, Ellen W %A Dennis, Joe %A Devilee, Peter %A Dörk, Thilo %A Dos-Santos-Silva, Isabel %A Dunning, Alison M %A Eicher, John D %A Fasching, Peter A %A Faul, Jessica D %A Figueroa, Jonine %A Flesch-Janys, Dieter %A Gandin, Ilaria %A Garcia, Melissa E %A García-Closas, Montserrat %A Giles, Graham G %A Girotto, Giorgia G %A Goldberg, Mark S %A González-Neira, Anna %A Goodarzi, Mark O %A Grove, Megan L %A Gudbjartsson, Daniel F %A Guenel, Pascal %A Guo, Xiuqing %A Haiman, Christopher A %A Hall, Per %A Hamann, Ute %A Henderson, Brian E %A Hocking, Lynne J %A Hofman, Albert %A Homuth, Georg %A Hooning, Maartje J %A Hopper, John L %A Hu, Frank B %A Huang, Jinyan %A Humphreys, Keith %A Hunter, David J %A Jakubowska, Anna %A Jones, Samuel E %A Kabisch, Maria %A Karasik, David %A Knight, Julia A %A Kolcic, Ivana %A Kooperberg, Charles %A Kosma, Veli-Matti %A Kriebel, Jennifer %A Kristensen, Vessela %A Lambrechts, Diether %A Langenberg, Claudia %A Li, Jingmei %A Li, Xin %A Lindström, Sara %A Liu, Yongmei %A Luan, Jian'an %A Lubinski, Jan %A Mägi, Reedik %A Mannermaa, Arto %A Manz, Judith %A Margolin, Sara %A Marten, Jonathan %A Martin, Nicholas G %A Masciullo, Corrado %A Meindl, Alfons %A Michailidou, Kyriaki %A Mihailov, Evelin %A Milani, Lili %A Milne, Roger L %A Müller-Nurasyid, Martina %A Nalls, Michael %A Neale, Benjamin M %A Nevanlinna, Heli %A Neven, Patrick %A Newman, Anne B %A Nordestgaard, Børge G %A Olson, Janet E %A Padmanabhan, Sandosh %A Peterlongo, Paolo %A Peters, Ulrike %A Petersmann, Astrid %A Peto, Julian %A Pharoah, Paul D P %A Pirastu, Nicola N %A Pirie, Ailith %A Pistis, Giorgio %A Polasek, Ozren %A Porteous, David %A Psaty, Bruce M %A Pylkäs, Katri %A Radice, Paolo %A Raffel, Leslie J %A Rivadeneira, Fernando %A Rudan, Igor %A Rudolph, Anja %A Ruggiero, Daniela %A Sala, Cinzia F %A Sanna, Serena %A Sawyer, Elinor J %A Schlessinger, David %A Schmidt, Marjanka K %A Schmidt, Frank %A Schmutzler, Rita K %A Schoemaker, Minouk J %A Scott, Robert A %A Seynaeve, Caroline M %A Simard, Jacques %A Sorice, Rossella %A Southey, Melissa C %A Stöckl, Doris %A Strauch, Konstantin %A Swerdlow, Anthony %A Taylor, Kent D %A Thorsteinsdottir, Unnur %A Toland, Amanda E %A Tomlinson, Ian %A Truong, Therese %A Tryggvadottir, Laufey %A Turner, Stephen T %A Vozzi, Diego %A Wang, Qin %A Wellons, Melissa %A Willemsen, Gonneke %A Wilson, James F %A Winqvist, Robert %A Wolffenbuttel, Bruce B H R %A Wright, Alan F %A Yannoukakos, Drakoulis %A Zemunik, Tatijana %A Zheng, Wei %A Zygmunt, Marek %A Bergmann, Sven %A Boomsma, Dorret I %A Buring, Julie E %A Ferrucci, Luigi %A Montgomery, Grant W %A Gudnason, Vilmundur %A Spector, Tim D %A van Duijn, Cornelia M %A Alizadeh, Behrooz Z %A Ciullo, Marina %A Crisponi, Laura %A Easton, Douglas F %A Gasparini, Paolo P %A Gieger, Christian %A Harris, Tamara B %A Hayward, Caroline %A Kardia, Sharon L R %A Kraft, Peter %A McKnight, Barbara %A Metspalu, Andres %A Morrison, Alanna C %A Reiner, Alex P %A Ridker, Paul M %A Rotter, Jerome I %A Toniolo, Daniela %A Uitterlinden, André G %A Ulivi, Sheila %A Völzke, Henry %A Wareham, Nicholas J %A Weir, David R %A Yerges-Armstrong, Laura M %A Price, Alkes L %A Stefansson, Kari %A Visser, Jenny A %A Ong, Ken K %A Chang-Claude, Jenny %A Murabito, Joanne M %A Perry, John R B %A Murray, Anna %X

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.

%B Nat Genet %V 47 %P 1294-303 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract %R 10.1038/ng.3412 %0 Journal Article %J Nat Commun %D 2015 %T Rare coding variants and X-linked loci associated with age at menarche. %A Lunetta, Kathryn L %A Day, Felix R %A Sulem, Patrick %A Ruth, Katherine S %A Tung, Joyce Y %A Hinds, David A %A Esko, Tõnu %A Elks, Cathy E %A Altmaier, Elisabeth %A He, Chunyan %A Huffman, Jennifer E %A Mihailov, Evelin %A Porcu, Eleonora %A Robino, Antonietta %A Rose, Lynda M %A Schick, Ursula M %A Stolk, Lisette %A Teumer, Alexander %A Thompson, Deborah J %A Traglia, Michela %A Wang, Carol A %A Yerges-Armstrong, Laura M %A Antoniou, Antonis C %A Barbieri, Caterina %A Coviello, Andrea D %A Cucca, Francesco %A Demerath, Ellen W %A Dunning, Alison M %A Gandin, Ilaria %A Grove, Megan L %A Gudbjartsson, Daniel F %A Hocking, Lynne J %A Hofman, Albert %A Huang, Jinyan %A Jackson, Rebecca D %A Karasik, David %A Kriebel, Jennifer %A Lange, Ethan M %A Lange, Leslie A %A Langenberg, Claudia %A Li, Xin %A Luan, Jian'an %A Mägi, Reedik %A Morrison, Alanna C %A Padmanabhan, Sandosh %A Pirie, Ailith %A Polasek, Ozren %A Porteous, David %A Reiner, Alex P %A Rivadeneira, Fernando %A Rudan, Igor %A Sala, Cinzia F %A Schlessinger, David %A Scott, Robert A %A Stöckl, Doris %A Visser, Jenny A %A Völker, Uwe %A Vozzi, Diego %A Wilson, James G %A Zygmunt, Marek %A Boerwinkle, Eric %A Buring, Julie E %A Crisponi, Laura %A Easton, Douglas F %A Hayward, Caroline %A Hu, Frank B %A Liu, Simin %A Metspalu, Andres %A Pennell, Craig E %A Ridker, Paul M %A Strauch, Konstantin %A Streeten, Elizabeth A %A Toniolo, Daniela %A Uitterlinden, André G %A Ulivi, Sheila %A Völzke, Henry %A Wareham, Nicholas J %A Wellons, Melissa %A Franceschini, Nora %A Chasman, Daniel I %A Thorsteinsdottir, Unnur %A Murray, Anna %A Stefansson, Kari %A Murabito, Joanne M %A Ong, Ken K %A Perry, John R B %X

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.

%B Nat Commun %V 6 %P 7756 %8 2015 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26239645?dopt=Abstract %R 10.1038/ncomms8756 %0 Journal Article %J Mutat Res %D 2015 %T Target sequencing approach intended to discover new mutations in non-syndromic intellectual disability. %A Morgan, Anna %A Gandin, Ilaria %A Belcaro, Chiara %A Palumbo, Pietro %A Palumbo, Orazio %A Biamino, Elisa %A Dal Col, Valentina %A Laurini, Erik %A Pricl, Sabrina %A Bosco, Paolo %A Carella, Massimo %A Ferrero, Giovanni Battista %A Romano, Corrado %A d'Adamo, Adamo Pio %A Faletra, Flavio %A Vozzi, Diego %X

The technological improvements over the last years made considerable progresses in the knowledge of the etiology of intellectual Disability (ID). However, at present very little is known about the genetic heterogeneity underlying the non-syndromic form of ID (NS-ID). To investigate the genetic basis of NS-ID we analyzed 43 trios and 22 isolated NS-ID patients using a targeted sequencing (TS) approach. 71 NS-ID genes have been selected and sequenced in all subjects. We found putative pathogenic mutations in 7 out of 65 patients. The pathogenic role of mutations was evaluated through sequence comparison and structural analysis was performed to predict the effect of alterations in a 3D computational model through molecular dynamics simulations. Additionally, a deep patient clinical re-evaluation has been performed after the molecular results. This approach allowed us to find novel pathogenic mutations with a detection rate close to 11% in our cohort of patients. This result supports the hypothesis that many NS-ID related genes still remain to be discovered and that NS-ID is a more complex phenotype compared to syndromic form, likely caused by a complex and broad interaction between genes alterations and environment factors.

%B Mutat Res %V 781 %P 32-6 %8 2015 Nov %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/26411299?dopt=Abstract %R 10.1016/j.mrfmmm.2015.09.002 %0 Journal Article %J J Am Soc Nephrol %D 2014 %T Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis. %A Olden, Matthias %A Corre, Tanguy %A Hayward, Caroline %A Toniolo, Daniela %A Ulivi, Sheila %A Gasparini, Paolo %A Pistis, Giorgio %A Hwang, Shih-Jen %A Bergmann, Sven %A Campbell, Harry %A Cocca, Massimiliano %A Gandin, Ilaria %A Girotto, Giorgia %A Glaudemans, Bob %A Hastie, Nicholas D %A Loffing, Johannes %A Polasek, Ozren %A Rampoldi, Luca %A Rudan, Igor %A Sala, Cinzia %A Traglia, Michela %A Vollenweider, Peter %A Vuckovic, Dragana %A Youhanna, Sonia %A Weber, Julien %A Wright, Alan F %A Kutalik, Zoltán %A Bochud, Murielle %A Fox, Caroline S %A Devuyst, Olivier %K Creatinine %K European Continental Ancestry Group %K Genetic Variation %K Humans %K Polymorphism, Single Nucleotide %K Uromodulin %X

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.

%B J Am Soc Nephrol %V 25 %P 1869-82 %8 2014 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/24578125?dopt=Abstract %R 10.1681/ASN.2013070781