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

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.

%B Nat Commun %V 9 %P 2904 %8 2018 07 25 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30046033?dopt=Abstract %R 10.1038/s41467-018-04766-9 %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 Am J Hum Genet %D 2017 %T Whole-Genome Sequencing Coupled to Imputation Discovers Genetic Signals for Anthropometric Traits. %A Tachmazidou, Ioanna %A Süveges, Dániel %A Min, Josine L %A Ritchie, Graham R S %A Steinberg, Julia %A Walter, Klaudia %A Iotchkova, Valentina %A Schwartzentruber, Jeremy %A Huang, Jie %A Memari, Yasin %A McCarthy, Shane %A Crawford, Andrew A %A Bombieri, Cristina %A Cocca, Massimiliano %A Farmaki, Aliki-Eleni %A Gaunt, Tom R %A Jousilahti, Pekka %A Kooijman, Marjolein N %A Lehne, Benjamin %A Malerba, Giovanni %A Männistö, Satu %A Matchan, Angela %A Medina-Gomez, Carolina %A Metrustry, Sarah J %A Nag, Abhishek %A Ntalla, Ioanna %A Paternoster, Lavinia %A Rayner, Nigel W %A Sala, Cinzia %A Scott, William R %A Shihab, Hashem A %A Southam, Lorraine %A St Pourcain, Beate %A Traglia, Michela %A Trajanoska, Katerina %A Zaza, Gialuigi %A Zhang, Weihua %A Artigas, María S %A Bansal, Narinder %A Benn, Marianne %A Chen, Zhongsheng %A Danecek, Petr %A Lin, Wei-Yu %A Locke, Adam %A Luan, Jian'an %A Manning, Alisa K %A Mulas, Antonella %A Sidore, Carlo %A Tybjaerg-Hansen, Anne %A Varbo, Anette %A Zoledziewska, Magdalena %A Finan, Chris %A Hatzikotoulas, Konstantinos %A Hendricks, Audrey E %A Kemp, John P %A Moayyeri, Alireza %A Panoutsopoulou, Kalliope %A Szpak, Michal %A Wilson, Scott G %A Boehnke, Michael %A Cucca, Francesco %A Di Angelantonio, Emanuele %A Langenberg, Claudia %A Lindgren, Cecilia %A McCarthy, Mark I %A Morris, Andrew P %A Nordestgaard, Børge G %A Scott, Robert A %A Tobin, Martin D %A Wareham, Nicholas J %A Burton, Paul %A Chambers, John C %A Smith, George Davey %A Dedoussis, George %A Felix, Janine F %A Franco, Oscar H %A Gambaro, Giovanni %A Gasparini, Paolo %A Hammond, Christopher J %A Hofman, Albert %A Jaddoe, Vincent W V %A Kleber, Marcus %A Kooner, Jaspal S %A Perola, Markus %A Relton, Caroline %A Ring, Susan M %A Rivadeneira, Fernando %A Salomaa, Veikko %A Spector, Timothy D %A Stegle, Oliver %A Toniolo, Daniela %A Uitterlinden, André G %A Barroso, Inês %A Greenwood, Celia M T %A Perry, John R B %A Walker, Brian R %A Butterworth, Adam S %A Xue, Yali %A Durbin, Richard %A Small, Kerrin S %A Soranzo, Nicole %A Timpson, Nicholas J %A Zeggini, Eleftheria %K Anthropometry %K Body Height %K Cohort Studies %K Databases, Genetic %K DNA Methylation %K Female %K Genetic Variation %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lipodystrophy %K Male %K Meta-Analysis as Topic %K Obesity %K Physical Chromosome Mapping %K Quantitative Trait Loci %K Sequence Analysis, DNA %K Sex Characteristics %K Syndrome %K United Kingdom %X

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.

%B Am J Hum Genet %V 100 %P 865-884 %8 2017 Jun 01 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/28552196?dopt=Abstract %R 10.1016/j.ajhg.2017.04.014 %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 Nat Genet %D 2015 %T Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. %A Sidore, Carlo %A Busonero, Fabio %A Maschio, Andrea %A Porcu, Eleonora %A Naitza, Silvia %A Zoledziewska, Magdalena %A Mulas, Antonella %A Pistis, Giorgio %A Steri, Maristella %A Danjou, Fabrice %A Kwong, Alan %A Ortega Del Vecchyo, Vicente Diego %A Chiang, Charleston W K %A Bragg-Gresham, Jennifer %A Pitzalis, Maristella %A Nagaraja, Ramaiah %A Tarrier, Brendan %A Brennan, Christine %A Uzzau, Sergio %A Fuchsberger, Christian %A Atzeni, Rossano %A Reinier, Frederic %A Berutti, Riccardo %A Huang, Jie %A Timpson, Nicholas J %A Toniolo, Daniela %A Gasparini, Paolo %A Malerba, Giovanni %A Dedoussis, George %A Zeggini, Eleftheria %A Soranzo, Nicole %A Jones, Chris %A Lyons, Robert %A Angius, Andrea %A Kang, Hyun M %A Novembre, John %A Sanna, Serena %A Schlessinger, David %A Cucca, Francesco %A Abecasis, Goncalo R %X

We report ∼17.6 million genetic variants from whole-genome sequencing of 2,120 Sardinians; 22% are absent from previous sequencing-based compilations and are enriched for predicted functional consequences. Furthermore, ∼76,000 variants common in our sample (frequency >5%) are rare elsewhere (<0.5% in the 1000 Genomes Project). We assessed the impact of these variants on circulating lipid levels and five inflammatory biomarkers. We observe 14 signals, including 2 major new loci, for lipid levels and 19 signals, including 2 new loci, for inflammatory markers. The new associations would have been missed in analyses based on 1000 Genomes Project data, underlining the advantages of large-scale sequencing in this founder population.

%B Nat Genet %V 47 %P 1272-81 %8 2015 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26366554?dopt=Abstract %R 10.1038/ng.3368 %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 Nat Genet %D 2013 %T Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. %A Köttgen, Anna %A Albrecht, Eva %A Teumer, Alexander %A Vitart, Veronique %A Krumsiek, Jan %A Hundertmark, Claudia %A Pistis, Giorgio %A Ruggiero, Daniela %A O'Seaghdha, Conall M %A Haller, Toomas %A Yang, Qiong %A Tanaka, Toshiko %A Johnson, Andrew D %A Kutalik, Zoltán %A Smith, Albert V %A Shi, Julia %A Struchalin, Maksim %A Middelberg, Rita P S %A Brown, Morris J %A Gaffo, Angelo L %A Pirastu, Nicola %A Li, Guo %A Hayward, Caroline %A Zemunik, Tatijana %A Huffman, Jennifer %A Yengo, Loic %A Zhao, Jing Hua %A Demirkan, Ayse %A Feitosa, Mary F %A Liu, Xuan %A Malerba, Giovanni %A Lopez, Lorna M %A van der Harst, Pim %A Li, Xinzhong %A Kleber, Marcus E %A Hicks, Andrew A %A Nolte, Ilja M %A Johansson, Åsa %A Murgia, Federico %A Wild, Sarah H %A Bakker, Stephan J L %A Peden, John F %A Dehghan, Abbas %A Steri, Maristella %A Tenesa, Albert %A Lagou, Vasiliki %A Salo, Perttu %A Mangino, Massimo %A Rose, Lynda M %A Lehtimäki, Terho %A Woodward, Owen M %A Okada, Yukinori %A Tin, Adrienne %A Müller, Christian %A Oldmeadow, Christopher %A Putku, Margus %A Czamara, Darina %A Kraft, Peter %A Frogheri, Laura %A Thun, Gian Andri %A Grotevendt, Anne %A Gislason, Gauti Kjartan %A Harris, Tamara B %A Launer, Lenore J %A McArdle, Patrick %A Shuldiner, Alan R %A Boerwinkle, Eric %A Coresh, Josef %A Schmidt, Helena %A Schallert, Michael %A Martin, Nicholas G %A Montgomery, Grant W %A Kubo, Michiaki %A Nakamura, Yusuke %A Tanaka, Toshihiro %A Munroe, Patricia B %A Samani, Nilesh J %A Jacobs, David R %A Liu, Kiang %A d'Adamo, Pio %A Ulivi, Sheila %A Rotter, Jerome I %A Psaty, Bruce M %A Vollenweider, Peter %A Waeber, Gerard %A Campbell, Susan %A Devuyst, Olivier %A Navarro, Pau %A Kolcic, Ivana %A Hastie, Nicholas %A Balkau, Beverley %A Froguel, Philippe %A Esko, Tõnu %A Salumets, Andres %A Khaw, Kay Tee %A Langenberg, Claudia %A Wareham, Nicholas J %A Isaacs, Aaron %A Kraja, Aldi %A Zhang, Qunyuan %A Wild, Philipp S %A Scott, Rodney J %A Holliday, Elizabeth G %A Org, Elin %A Viigimaa, Margus %A Bandinelli, Stefania %A Metter, Jeffrey E %A Lupo, Antonio %A Trabetti, Elisabetta %A Sorice, Rossella %A Döring, Angela %A Lattka, Eva %A Strauch, Konstantin %A Theis, Fabian %A Waldenberger, Melanie %A Wichmann, H-Erich %A Davies, Gail %A Gow, Alan J %A Bruinenberg, Marcel %A Stolk, Ronald P %A Kooner, Jaspal S %A Zhang, Weihua %A Winkelmann, Bernhard R %A Boehm, Bernhard O %A Lucae, Susanne %A Penninx, Brenda W %A Smit, Johannes H %A Curhan, Gary %A Mudgal, Poorva %A Plenge, Robert M %A Portas, Laura %A Persico, Ivana %A Kirin, Mirna %A Wilson, James F %A Mateo Leach, Irene %A van Gilst, Wiek H %A Goel, Anuj %A Ongen, Halit %A Hofman, Albert %A Rivadeneira, Fernando %A Uitterlinden, André G %A Imboden, Medea %A von Eckardstein, Arnold %A Cucca, Francesco %A Nagaraja, Ramaiah %A Piras, Maria Grazia %A Nauck, Matthias %A Schurmann, Claudia %A Budde, Kathrin %A Ernst, Florian %A Farrington, Susan M %A Theodoratou, Evropi %A Prokopenko, Inga %A Stumvoll, Michael %A Jula, Antti %A Perola, Markus %A Salomaa, Veikko %A Shin, So-Youn %A Spector, Tim D %A Sala, Cinzia %A Ridker, Paul M %A Kähönen, Mika %A Viikari, Jorma %A Hengstenberg, Christian %A Nelson, Christopher P %A Meschia, James F %A Nalls, Michael A %A Sharma, Pankaj %A Singleton, Andrew B %A Kamatani, Naoyuki %A Zeller, Tanja %A Burnier, Michel %A Attia, John %A Laan, Maris %A Klopp, Norman %A Hillege, Hans L %A Kloiber, Stefan %A Choi, Hyon %A Pirastu, Mario %A Tore, Silvia %A Probst-Hensch, Nicole M %A Völzke, Henry %A Gudnason, Vilmundur %A Parsa, Afshin %A Schmidt, Reinhold %A Whitfield, John B %A Fornage, Myriam %A Gasparini, Paolo %A Siscovick, David S %A Polasek, Ozren %A Campbell, Harry %A Rudan, Igor %A Bouatia-Naji, Nabila %A Metspalu, Andres %A Loos, Ruth J F %A van Duijn, Cornelia M %A Borecki, Ingrid B %A Ferrucci, Luigi %A Gambaro, Giovanni %A Deary, Ian J %A Wolffenbuttel, Bruce H R %A Chambers, John C %A März, Winfried %A Pramstaller, Peter P %A Snieder, Harold %A Gyllensten, Ulf %A Wright, Alan F %A Navis, Gerjan %A Watkins, Hugh %A Witteman, Jacqueline C M %A Sanna, Serena %A Schipf, Sabine %A Dunlop, Malcolm G %A Tönjes, Anke %A Ripatti, Samuli %A Soranzo, Nicole %A Toniolo, Daniela %A Chasman, Daniel I %A Raitakari, Olli %A Kao, W H Linda %A Ciullo, Marina %A Fox, Caroline S %A Caulfield, Mark %A Bochud, Murielle %A Gieger, Christian %K Analysis of Variance %K European Continental Ancestry Group %K Gene Frequency %K Genetic Loci %K Genome-Wide Association Study %K Glucose %K Gout %K Humans %K Inhibins %K Polymorphism, Single Nucleotide %K Signal Transduction %K Uric Acid %X

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.

%B Nat Genet %V 45 %P 145-54 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract %R 10.1038/ng.2500