TY - JOUR T1 - Multiple loci associated with indices of renal function and chronic kidney disease. JF - Nat Genet Y1 - 2009 A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Katz, Ronit A1 - Li, Man A1 - Yang, Qiong A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Arking, Dan E A1 - Astor, Brad C A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Ruczinski, Ingo A1 - Scharpf, Robert B A1 - Chen, Yii-Der Ida A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Sarnak, Mark A1 - Siscovick, David A1 - Benjamin, Emelia J A1 - Levy, Daniel A1 - Upadhyay, Ashish A1 - Aulchenko, Yurii S A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Chasman, Daniel I A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Fox, Caroline S KW - Chromosome Mapping KW - Cohort Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Meta-Analysis as Topic KW - Mucoproteins KW - Netherlands KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Uromodulin AB -

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract ER - TY - JOUR T1 - Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. JF - Nat Genet Y1 - 2010 A1 - Speliotes, Elizabeth K A1 - Willer, Cristen J A1 - Berndt, Sonja I A1 - Monda, Keri L A1 - Thorleifsson, Gudmar A1 - Jackson, Anne U A1 - Lango Allen, Hana A1 - Lindgren, Cecilia M A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Workalemahu, Tsegaselassie A1 - Heid, Iris M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Weedon, Michael N A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Ferreira, Teresa A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Estrada, Karol A1 - Liang, Liming A1 - Nemesh, James A1 - Park, Ju-Hyun A1 - Gustafsson, Stefan A1 - Kilpeläinen, Tuomas O A1 - Yang, Jian A1 - Bouatia-Naji, Nabila A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Kutalik, Zoltán A1 - Mangino, Massimo A1 - Raychaudhuri, Soumya A1 - Scherag, Andre A1 - Smith, Albert Vernon A1 - Welch, Ryan A1 - Zhao, Jing Hua A1 - Aben, Katja K A1 - Absher, Devin M A1 - Amin, Najaf A1 - Dixon, Anna L A1 - Fisher, Eva A1 - Glazer, Nicole L A1 - Goddard, Michael E A1 - Heard-Costa, Nancy L A1 - Hoesel, Volker A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Lamina, Claudia A1 - Li, Shengxu A1 - Moffatt, Miriam F A1 - Myers, Richard H A1 - Narisu, Narisu A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan P A1 - van Wingerden, Sophie A1 - Watanabe, Richard M A1 - White, Charles C A1 - Wiklund, Fredrik A1 - Barlassina, Christina A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Prokopenko, Inga A1 - Shi, Jianxin A1 - Thiering, Elisabeth A1 - Alavere, Helene A1 - Alibrandi, Maria T S A1 - Almgren, Peter A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Atwood, Larry D A1 - Balkau, Beverley A1 - Balmforth, Anthony J A1 - Bennett, Amanda J A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Biebermann, Heike A1 - Blakemore, Alexandra I F A1 - Boes, Tanja A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Brown, Morris J A1 - Buchanan, Thomas A A1 - Busonero, Fabio A1 - Campbell, Harry A1 - Cappuccio, Francesco P A1 - Cavalcanti-Proença, Christine A1 - Chen, Yii-Der Ida A1 - Chen, Chih-Mei A1 - Chines, Peter S A1 - Clarke, Robert A1 - Coin, Lachlan A1 - Connell, John A1 - Day, Ian N M A1 - den Heijer, Martin A1 - Duan, Jubao A1 - Ebrahim, Shah A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eiriksdottir, Gudny A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Facheris, Maurizio F A1 - Felix, Stephan B A1 - Fischer-Posovszky, Pamela A1 - Folsom, Aaron R A1 - Friedrich, Nele A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Gejman, Pablo V A1 - Geus, Eco J C A1 - Gieger, Christian A1 - Gjesing, Anette P A1 - Goel, Anuj A1 - Goyette, Philippe A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Greenawalt, Danielle M A1 - Groves, Christopher J A1 - Gudnason, Vilmundur A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hall, Alistair S A1 - Havulinna, Aki S A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hinney, Anke A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jacobs, Kevin B A1 - Jarick, Ivonne A1 - Jewell, Elizabeth A1 - John, Ulrich A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kaakinen, Marika A1 - Kajantie, Eero A1 - Kaplan, Lee M A1 - Kathiresan, Sekar A1 - Kettunen, Johannes A1 - Kinnunen, Leena A1 - Knowles, Joshua W A1 - Kolcic, Ivana A1 - König, Inke R A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kuusisto, Johanna A1 - Kraft, Peter A1 - Kvaløy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lanzani, Chiara A1 - Launer, Lenore J A1 - Lecoeur, Cécile A1 - Lehtimäki, Terho A1 - Lettre, Guillaume A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - Manunta, Paolo A1 - Marek, Diana A1 - Marre, Michel A1 - Martin, Nicholas G A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - McKnight, Barbara A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Meyre, David A1 - Midthjell, Kristian A1 - Montgomery, Grant W A1 - Morken, Mario A A1 - Morris, Andrew P A1 - Mulic, Rosanda A1 - Ngwa, Julius S A1 - Nelis, Mari A1 - Neville, Matt J A1 - Nyholt, Dale R A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Ong, Ken K A1 - Oostra, Ben A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Perola, Markus A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Rafelt, Suzanne A1 - Raitakari, Olli A1 - Rayner, Nigel W A1 - Ridderstråle, Martin A1 - Rief, Winfried A1 - Ruokonen, Aimo A1 - Robertson, Neil R A1 - Rzehak, Peter A1 - Salomaa, Veikko A1 - Sanders, Alan R A1 - Sandhu, Manjinder S A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Savolainen, Markku J A1 - Scherag, Susann A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Silander, Kaisa A1 - Sinisalo, Juha A1 - Siscovick, David S A1 - Smit, Jan H A1 - Soranzo, Nicole A1 - Sovio, Ulla A1 - Stephens, Jonathan A1 - Surakka, Ida A1 - Swift, Amy J A1 - Tammesoo, Mari-Liis A1 - Tardif, Jean-Claude A1 - Teder-Laving, Maris A1 - Teslovich, Tanya M A1 - Thompson, John R A1 - Thomson, Brian A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Viikari, Jorma A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogel, Carla I G A1 - Voight, Benjamin F A1 - Waite, Lindsay L A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wiegand, Susanna A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Witteman, Jacqueline C A1 - Xu, Jianfeng A1 - Zhang, Qunyuan A1 - Zgaga, Lina A1 - Ziegler, Andreas A1 - Zitting, Paavo A1 - Beilby, John P A1 - Farooqi, I Sadaf A1 - Hebebrand, Johannes A1 - Huikuri, Heikki V A1 - James, Alan L A1 - Kähönen, Mika A1 - Levinson, Douglas F A1 - Macciardi, Fabio A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Beckmann, Jacques S A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Collins, Francis S A1 - Cupples, L Adrienne A1 - Smith, George Davey A1 - Erdmann, Jeanette A1 - Froguel, Philippe A1 - Grönberg, Henrik A1 - Gyllensten, Ulf A1 - Hall, Per A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayes, Richard B A1 - Heinrich, Joachim A1 - Hu, Frank B A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Kaprio, Jaakko A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Kiemeney, Lambertus A A1 - Krude, Heiko A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Metspalu, Andres A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Pedersen, Oluf A1 - Penninx, Brenda W A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Reinehr, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Schwarz, Peter E H A1 - Shuldiner, Alan R A1 - Spector, Timothy D A1 - Tuomilehto, Jaakko A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Valle, Timo T A1 - Wabitsch, Martin A1 - Waeber, Gérard A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Chatterjee, Nilanjan A1 - McCarroll, Steven A A1 - Purcell, Shaun A1 - Schadt, Eric E A1 - Visscher, Peter M A1 - Assimes, Themistocles L A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - van Duijn, Cornelia M A1 - Wichmann, H-Erich A1 - Frayling, Timothy M A1 - Thorsteinsdottir, Unnur A1 - Abecasis, Goncalo R A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Stefansson, Kari A1 - North, Kari E A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Ingelsson, Erik A1 - Loos, Ruth J F KW - Body Height KW - Body Mass Index KW - Body Size KW - Body Weight KW - Chromosome Mapping KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Obesity KW - Polymorphism, Single Nucleotide AB -

Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935630?dopt=Abstract ER - TY - JOUR T1 - Biological, clinical and population relevance of 95 loci for blood lipids. JF - Nature Y1 - 2010 A1 - Teslovich, Tanya M A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Ripatti, Samuli A1 - Chasman, Daniel I A1 - Willer, Cristen J A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Isaacs, Aaron A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - Feitosa, Mary F A1 - Chambers, John A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Johnson, Toby A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Li, Mingyao A1 - Shin Cho, Yoon A1 - Jin Go, Min A1 - Jin Kim, Young A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Twee-Hee Ong, Rick A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Song, Kijoung A1 - Hua Zhao, Jing A1 - Yuan, Xin A1 - Luan, Jian'an A1 - Lamina, Claudia A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Wright, Alan F A1 - Witteman, Jacqueline C M A1 - Wilson, James F A1 - Willemsen, Gonneke A1 - Wichmann, H-Erich A1 - Whitfield, John B A1 - Waterworth, Dawn M A1 - Wareham, Nicholas J A1 - Waeber, Gérard A1 - Vollenweider, Peter A1 - Voight, Benjamin F A1 - Vitart, Veronique A1 - Uitterlinden, André G A1 - Uda, Manuela A1 - Tuomilehto, Jaakko A1 - Thompson, John R A1 - Tanaka, Toshiko A1 - Surakka, Ida A1 - Stringham, Heather M A1 - Spector, Tim D A1 - Soranzo, Nicole A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Silander, Kaisa A1 - Sijbrands, Eric J G A1 - Scuteri, Angelo A1 - Scott, James A1 - Schlessinger, David A1 - Sanna, Serena A1 - Salomaa, Veikko A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Ruokonen, Aimo A1 - Rudan, Igor A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Psaty, Bruce M A1 - Pramstaller, Peter P A1 - Pichler, Irene A1 - Perola, Markus A1 - Penninx, Brenda W J H A1 - Pedersen, Nancy L A1 - Pattaro, Cristian A1 - Parker, Alex N A1 - Paré, Guillaume A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - Meitinger, Thomas A1 - McPherson, Ruth A1 - McCarthy, Mark I A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Mangino, Massimo A1 - Magnusson, Patrik K E A1 - Lucas, Gavin A1 - Luben, Robert A1 - Loos, Ruth J F A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - Kronenberg, Florian A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaprio, Jaakko A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Jarvelin, Marjo-Riitta A1 - Janssens, A Cecile J W A1 - Ingelsson, Erik A1 - Igl, Wilmar A1 - Kees Hovingh, G A1 - Hottenga, Jouke-Jan A1 - Hofman, Albert A1 - Hicks, Andrew A A1 - Hengstenberg, Christian A1 - Heid, Iris M A1 - Hayward, Caroline A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Gyllensten, Ulf A1 - Guiducci, Candace A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Gieger, Christian A1 - Freimer, Nelson B A1 - Ferrucci, Luigi A1 - Erdmann, Jeanette A1 - Elliott, Paul A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Geus, Eco J C A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Collins, Francis S A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Campbell, Harry A1 - Burtt, Noel P A1 - Bonnycastle, Lori L A1 - Boomsma, Dorret I A1 - Boekholdt, S Matthijs A1 - Bergman, Richard N A1 - Barroso, Inês A1 - Bandinelli, Stefania A1 - Ballantyne, Christie M A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Altshuler, David A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Adair, Linda S A1 - Taylor, Herman A A1 - Borecki, Ingrid B A1 - Gabriel, Stacey B A1 - Wilson, James G A1 - Holm, Hilma A1 - Thorsteinsdottir, Unnur A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Mohlke, Karen L A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Strachan, David P A1 - Mooser, Vincent A1 - Stefansson, Kari A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Kathiresan, Sekar KW - African Americans KW - Animals KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipid Metabolism KW - Lipids KW - Liver KW - Male KW - Mice KW - N-Acetylgalactosaminyltransferases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Protein Phosphatase 1 KW - Reproducibility of Results KW - Triglycerides AB -

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

VL - 466 IS - 7307 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20686565?dopt=Abstract ER - TY - JOUR T1 - Hundreds of variants clustered in genomic loci and biological pathways affect human height. JF - Nature Y1 - 2010 A1 - Lango Allen, Hana A1 - Estrada, Karol A1 - Lettre, Guillaume A1 - Berndt, Sonja I A1 - Weedon, Michael N A1 - Rivadeneira, Fernando A1 - Willer, Cristen J A1 - Jackson, Anne U A1 - Vedantam, Sailaja A1 - Raychaudhuri, Soumya A1 - Ferreira, Teresa A1 - Wood, Andrew R A1 - Weyant, Robert J A1 - Segrè, Ayellet V A1 - Speliotes, Elizabeth K A1 - Wheeler, Eleanor A1 - Soranzo, Nicole A1 - Park, Ju-Hyun A1 - Yang, Jian A1 - Gudbjartsson, Daniel A1 - Heard-Costa, Nancy L A1 - Randall, Joshua C A1 - Qi, Lu A1 - Vernon Smith, Albert A1 - Mägi, Reedik A1 - Pastinen, Tomi A1 - Liang, Liming A1 - Heid, Iris M A1 - Luan, Jian'an A1 - Thorleifsson, Gudmar A1 - Winkler, Thomas W A1 - Goddard, Michael E A1 - Sin Lo, Ken A1 - Palmer, Cameron A1 - Workalemahu, Tsegaselassie A1 - Aulchenko, Yurii S A1 - Johansson, Asa A1 - Zillikens, M Carola A1 - Feitosa, Mary F A1 - Esko, Tõnu A1 - Johnson, Toby A1 - Ketkar, Shamika A1 - Kraft, Peter A1 - Mangino, Massimo A1 - Prokopenko, Inga A1 - Absher, Devin A1 - Albrecht, Eva A1 - Ernst, Florian A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Hottenga, Jouke-Jan A1 - Jacobs, Kevin B A1 - Knowles, Joshua W A1 - Kutalik, Zoltán A1 - Monda, Keri L A1 - Polasek, Ozren A1 - Preuss, Michael A1 - Rayner, Nigel W A1 - Robertson, Neil R A1 - Steinthorsdottir, Valgerdur A1 - Tyrer, Jonathan P A1 - Voight, Benjamin F A1 - Wiklund, Fredrik A1 - Xu, Jianfeng A1 - Zhao, Jing Hua A1 - Nyholt, Dale R A1 - Pellikka, Niina A1 - Perola, Markus A1 - Perry, John R B A1 - Surakka, Ida A1 - Tammesoo, Mari-Liis A1 - Altmaier, Elizabeth L A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Bhangale, Tushar A1 - Boucher, Gabrielle A1 - Chasman, Daniel I A1 - Chen, Constance A1 - Coin, Lachlan A1 - Cooper, Matthew N A1 - Dixon, Anna L A1 - Gibson, Quince A1 - Grundberg, Elin A1 - Hao, Ke A1 - Juhani Junttila, M A1 - Kaplan, Lee M A1 - Kettunen, Johannes A1 - König, Inke R A1 - Kwan, Tony A1 - Lawrence, Robert W A1 - Levinson, Douglas F A1 - Lorentzon, Mattias A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Müller, Martina A1 - Suh Ngwa, Julius A1 - Purcell, Shaun A1 - Rafelt, Suzanne A1 - Salem, Rany M A1 - Salvi, Erika A1 - Sanna, Serena A1 - Shi, Jianxin A1 - Sovio, Ulla A1 - Thompson, John R A1 - Turchin, Michael C A1 - Vandenput, Liesbeth A1 - Verlaan, Dominique J A1 - Vitart, Veronique A1 - White, Charles C A1 - Ziegler, Andreas A1 - Almgren, Peter A1 - Balmforth, Anthony J A1 - Campbell, Harry A1 - Citterio, Lorena A1 - De Grandi, Alessandro A1 - Dominiczak, Anna A1 - Duan, Jubao A1 - Elliott, Paul A1 - Elosua, Roberto A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Geus, Eco J C A1 - Glorioso, Nicola A1 - Haiqing, Shen A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Illig, Thomas A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kilpeläinen, Tuomas O A1 - Koiranen, Markku A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Laitinen, Jaana A1 - Liu, Jianjun A1 - Lokki, Marja-Liisa A1 - Marusic, Ana A1 - Maschio, Andrea A1 - Meitinger, Thomas A1 - Mulas, Antonella A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Petersmann, Astrid A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Rotter, Jerome I A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Schmidt, Carsten Oliver A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Stringham, Heather M A1 - Bragi Walters, G A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Zagato, Laura A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Alavere, Helene A1 - Farrall, Martin A1 - McArdle, Wendy L A1 - Nelis, Mari A1 - Peters, Marjolein J A1 - Ripatti, Samuli A1 - van Meurs, Joyce B J A1 - Aben, Katja K A1 - Ardlie, Kristin G A1 - Beckmann, Jacques S A1 - Beilby, John P A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Collins, Francis S A1 - Cusi, Daniele A1 - den Heijer, Martin A1 - Eiriksdottir, Gudny A1 - Gejman, Pablo V A1 - Hall, Alistair S A1 - Hamsten, Anders A1 - Huikuri, Heikki V A1 - Iribarren, Carlos A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kathiresan, Sekar A1 - Kiemeney, Lambertus A1 - Kocher, Thomas A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Melander, Olle A1 - Mosley, Tom H A1 - Musk, Arthur W A1 - Nieminen, Markku S A1 - O'Donnell, Christopher J A1 - Ohlsson, Claes A1 - Oostra, Ben A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Rioux, John D A1 - Rissanen, Aila A1 - Rivolta, Carlo A1 - Schunkert, Heribert A1 - Shuldiner, Alan R A1 - Siscovick, David S A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - van Ommen, Gert-Jan A1 - Viikari, Jorma A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Province, Michael A A1 - Kayser, Manfred A1 - Arnold, Alice M A1 - Atwood, Larry D A1 - Boerwinkle, Eric A1 - Chanock, Stephen J A1 - Deloukas, Panos A1 - Gieger, Christian A1 - Grönberg, Henrik A1 - Hall, Per A1 - Hattersley, Andrew T A1 - Hengstenberg, Christian A1 - Hoffman, Wolfgang A1 - Lathrop, G Mark A1 - Salomaa, Veikko A1 - Schreiber, Stefan A1 - Uda, Manuela A1 - Waterworth, Dawn A1 - Wright, Alan F A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Hofman, Albert A1 - Mohlke, Karen L A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Cupples, L Adrienne A1 - Erdmann, Jeanette A1 - Fox, Caroline S A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hayes, Richard B A1 - Jarvelin, Marjo-Riitta A1 - Mooser, Vincent A1 - Munroe, Patricia B A1 - Ouwehand, Willem H A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Quertermous, Thomas A1 - Rudan, Igor A1 - Samani, Nilesh J A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Wilson, James F A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hu, Frank B A1 - Kaplan, Robert C A1 - Metspalu, Andres A1 - North, Kari E A1 - Schlessinger, David A1 - Wareham, Nicholas J A1 - Hunter, David J A1 - O'Connell, Jeffrey R A1 - Strachan, David P A1 - Wichmann, H-Erich A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Schadt, Eric E A1 - Thorsteinsdottir, Unnur A1 - Peltonen, Leena A1 - Uitterlinden, André G A1 - Visscher, Peter M A1 - Chatterjee, Nilanjan A1 - Loos, Ruth J F A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Lindgren, Cecilia M A1 - Abecasis, Goncalo R A1 - Stefansson, Kari A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N KW - Body Height KW - Chromosomes, Human, Pair 3 KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Metabolic Networks and Pathways KW - Multifactorial Inheritance KW - Phenotype KW - Polymorphism, Single Nucleotide AB -

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

VL - 467 IS - 7317 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20881960?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. JF - Nat Genet Y1 - 2010 A1 - Heid, Iris M A1 - Jackson, Anne U A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Qi, Lu A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Zillikens, M Carola A1 - Speliotes, Elizabeth K A1 - Mägi, Reedik A1 - Workalemahu, Tsegaselassie A1 - White, Charles C A1 - Bouatia-Naji, Nabila A1 - Harris, Tamara B A1 - Berndt, Sonja I A1 - Ingelsson, Erik A1 - Willer, Cristen J A1 - Weedon, Michael N A1 - Luan, Jian'an A1 - Vedantam, Sailaja A1 - Esko, Tõnu A1 - Kilpeläinen, Tuomas O A1 - Kutalik, Zoltán A1 - Li, Shengxu A1 - Monda, Keri L A1 - Dixon, Anna L A1 - Holmes, Christopher C A1 - Kaplan, Lee M A1 - Liang, Liming A1 - Min, Josine L A1 - Moffatt, Miriam F A1 - Molony, Cliona A1 - Nicholson, George A1 - Schadt, Eric E A1 - Zondervan, Krina T A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Lango Allen, Hana A1 - Weyant, Robert J A1 - Wheeler, Eleanor A1 - Wood, Andrew R A1 - Estrada, Karol A1 - Goddard, Michael E A1 - Lettre, Guillaume A1 - Mangino, Massimo A1 - Nyholt, Dale R A1 - Purcell, Shaun A1 - Smith, Albert Vernon A1 - Visscher, Peter M A1 - Yang, Jian A1 - McCarroll, Steven A A1 - Nemesh, James A1 - Voight, Benjamin F A1 - Absher, Devin A1 - Amin, Najaf A1 - Aspelund, Thor A1 - Coin, Lachlan A1 - Glazer, Nicole L A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kapur, Karen A1 - Ketkar, Shamika A1 - Knowles, Joshua W A1 - Kraft, Peter A1 - Kraja, Aldi T A1 - Lamina, Claudia A1 - Leitzmann, Michael F A1 - McKnight, Barbara A1 - Morris, Andrew P A1 - Ong, Ken K A1 - Perry, John R B A1 - Peters, Marjolein J A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Rayner, Nigel W A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Robertson, Neil R A1 - Sanna, Serena A1 - Sovio, Ulla A1 - Surakka, Ida A1 - Teumer, Alexander A1 - van Wingerden, Sophie A1 - Vitart, Veronique A1 - Zhao, Jing Hua A1 - Cavalcanti-Proença, Christine A1 - Chines, Peter S A1 - Fisher, Eva A1 - Kulzer, Jennifer R A1 - Lecoeur, Cécile A1 - Narisu, Narisu A1 - Sandholt, Camilla A1 - Scott, Laura J A1 - Silander, Kaisa A1 - Stark, Klaus A1 - Tammesoo, Mari-Liis A1 - Teslovich, Tanya M A1 - Timpson, Nicholas John A1 - Watanabe, Richard M A1 - Welch, Ryan A1 - Chasman, Daniel I A1 - Cooper, Matthew N A1 - Jansson, John-Olov A1 - Kettunen, Johannes A1 - Lawrence, Robert W A1 - Pellikka, Niina A1 - Perola, Markus A1 - Vandenput, Liesbeth A1 - Alavere, Helene A1 - Almgren, Peter A1 - Atwood, Larry D A1 - Bennett, Amanda J A1 - Biffar, Reiner A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Buchanan, Thomas A A1 - Campbell, Harry A1 - Day, Ian N M A1 - Dei, Mariano A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Erdos, Michael R A1 - Eriksson, Johan G A1 - Freimer, Nelson B A1 - Fu, Mao A1 - Gaget, Stefan A1 - Geus, Eco J C A1 - Gjesing, Anette P A1 - Grallert, Harald A1 - Grässler, Jürgen A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Havulinna, Aki S A1 - Herzig, Karl-Heinz A1 - Hicks, Andrew A A1 - Hui, Jennie A1 - Igl, Wilmar A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kajantie, Eero A1 - Kinnunen, Leena A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kroemer, Heyo K A1 - Krzelj, Vjekoslav A1 - Kuusisto, Johanna A1 - Kvaloy, Kirsti A1 - Laitinen, Jaana A1 - Lantieri, Olivier A1 - Lathrop, G Mark A1 - Lokki, Marja-Liisa A1 - Luben, Robert N A1 - Ludwig, Barbara A1 - McArdle, Wendy L A1 - McCarthy, Anne A1 - Morken, Mario A A1 - Nelis, Mari A1 - Neville, Matt J A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Peden, John F A1 - Pichler, Irene A1 - Pietiläinen, Kirsi H A1 - Platou, Carl G P A1 - Pouta, Anneli A1 - Ridderstråle, Martin A1 - Samani, Nilesh J A1 - Saramies, Jouko A1 - Sinisalo, Juha A1 - Smit, Jan H A1 - Strawbridge, Rona J A1 - Stringham, Heather M A1 - Swift, Amy J A1 - Teder-Laving, Maris A1 - Thomson, Brian A1 - Usala, Gianluca A1 - van Meurs, Joyce B J A1 - van Ommen, Gert-Jan A1 - Vatin, Vincent A1 - Volpato, Claudia B A1 - Wallaschofski, Henri A1 - Walters, G Bragi A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witte, Daniel R A1 - Zgaga, Lina A1 - Zitting, Paavo A1 - Beilby, John P A1 - James, Alan L A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Palmer, Lyle J A1 - Raitakari, Olli A1 - Ridker, Paul M A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Viikari, Jorma A1 - Balkau, Beverley A1 - Ben-Shlomo, Yoav A1 - Bergman, Richard N A1 - Boeing, Heiner A1 - Smith, George Davey A1 - Ebrahim, Shah A1 - Froguel, Philippe A1 - Hansen, Torben A1 - Hengstenberg, Christian A1 - Hveem, Kristian A1 - Isomaa, Bo A1 - Jørgensen, Torben A1 - Karpe, Fredrik A1 - Khaw, Kay-Tee A1 - Laakso, Markku A1 - Lawlor, Debbie A A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Midthjell, Kristian A1 - Pedersen, Oluf A1 - Salomaa, Veikko A1 - Schwarz, Peter E H A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Wareham, Nicholas J A1 - Arnold, Alice M A1 - Beckmann, Jacques S A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Collins, Francis S A1 - Eiriksdottir, Gudny A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Hattersley, Andrew T A1 - Hofman, Albert A1 - Hu, Frank B A1 - Illig, Thomas A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Kao, W H Linda A1 - Kaprio, Jaakko A1 - Launer, Lenore J A1 - Munroe, Patricia B A1 - Oostra, Ben A1 - Penninx, Brenda W A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rissanen, Aila A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Syvänen, Ann-Christine A1 - Uda, Manuela A1 - Uitterlinden, Andre A1 - Völzke, Henry A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Wright, Alan F A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Frayling, Timothy M A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David J A1 - Kaplan, Robert C A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Peltonen, Leena A1 - Schlessinger, David A1 - Strachan, David P A1 - Hirschhorn, Joel N A1 - Assimes, Themistocles L A1 - Wichmann, H-Erich A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Cupples, L Adrienne A1 - Loos, Ruth J F A1 - Barroso, Inês A1 - McCarthy, Mark I A1 - Fox, Caroline S A1 - Mohlke, Karen L A1 - Lindgren, Cecilia M KW - Adipose Tissue KW - Age Factors KW - Chromosome Mapping KW - Female KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist-Hip Ratio AB -

Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20935629?dopt=Abstract ER - TY - JOUR T1 - Multiple genetic loci influence serum urate levels and their relationship with gout and cardiovascular disease risk factors. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Yang, Qiong A1 - Köttgen, Anna A1 - Dehghan, Abbas A1 - Smith, Albert V A1 - Glazer, Nicole L A1 - Chen, Ming-Huei A1 - Chasman, Daniel I A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore A1 - Nalls, Michael A1 - Hernandez, Dena A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Grove, Megan L A1 - Li, Man A1 - Linda Kao, W H A1 - Chonchol, Michel A1 - Haritunians, Talin A1 - Li, Guo A1 - Lumley, Thomas A1 - Psaty, Bruce M A1 - Shlipak, Michael A1 - Hwang, Shih-Jen A1 - Larson, Martin G A1 - O'Donnell, Christopher J A1 - Upadhyay, Ashish A1 - van Duijn, Cornelia M A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Stricker, Bruno A1 - Uitterlinden, André G A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Ridker, Paul M A1 - Siscovick, David S A1 - Gudnason, Vilmundur A1 - Witteman, Jacqueline C A1 - Fox, Caroline S A1 - Coresh, Josef KW - Cardiovascular Diseases KW - Coronary Disease KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Gout KW - Humans KW - Male KW - Risk Factors KW - Uric Acid AB -

BACKGROUND: Elevated serum urate levels can lead to gout and are associated with cardiovascular risk factors. We performed a genome-wide association study to search for genetic susceptibility loci for serum urate and gout and investigated the causal nature of the associations of serum urate with gout and selected cardiovascular risk factors and coronary heart disease (CHD).

METHODS AND RESULTS: Meta-analyses of genome-wide association studies (GWAS) were performed in 5 population-based cohorts of the Cohorts for Heart and Aging Research in Genome Epidemiology consortium for serum urate and gout in 28 283 white participants. The effect of the most significant single-nucleotide polymorphism at all genome-wide significant loci on serum urate was added to create a genetic urate score. Findings were replicated in the Women's Genome Health Study (n=22 054). Single-nucleotide polymorphisms at 8 genetic loci achieved genome-wide significance with serum urate levels (P=4×10(-8) to 2×10(-242) in SLC22A11, GCKR, R3HDM2-INHBC region, RREB1, PDZK1, SLC2A9, ABCG2, and SLC17A1). Only 2 loci (SLC2A9, ABCG2) showed genome-wide significant association with gout. The genetic urate score was strongly associated with serum urate and gout (odds ratio, 12.4 per 100 μmol/L; P=3×10(-39)) but not with blood pressure, glucose, estimated glomerular filtration rate, chronic kidney disease, or CHD. The lack of association between the genetic score and the latter phenotypes also was observed in the Women's Genome Health Study.

CONCLUSIONS: The genetic urate score analysis suggested a causal relationship between serum urate and gout but did not provide evidence for one between serum urate and cardiovascular risk factors and CHD.

VL - 3 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20884846?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. JF - PLoS Genet Y1 - 2011 A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Rose, Lynda A1 - Barbalic, Maja A1 - Dupuis, Josée A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - Benjamin, Emelia J A1 - Shiffman, Dov A1 - Parker, Alexander N A1 - Chasman, Daniel I KW - ABO Blood-Group System KW - Cohort Studies KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - I-kappa B Kinase KW - Intercellular Adhesion Molecule-1 KW - Lipase KW - Membrane Proteins KW - Models, Genetic KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide KW - Proteins KW - Transcription Factor RelA AB -

Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P  =  5.8 × 10(-9)), RELA (rs1049728, P =  2.7 × 10(-16)), and SH2B3 (rs3184504, P =  2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21533024?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. JF - Circulation Y1 - 2011 A1 - Dehghan, Abbas A1 - Dupuis, Josée A1 - Barbalic, Maja A1 - Bis, Joshua C A1 - Eiriksdottir, Gudny A1 - Lu, Chen A1 - Pellikka, Niina A1 - Wallaschofski, Henri A1 - Kettunen, Johannes A1 - Henneman, Peter A1 - Baumert, Jens A1 - Strachan, David P A1 - Fuchsberger, Christian A1 - Vitart, Veronique A1 - Wilson, James F A1 - Paré, Guillaume A1 - Naitza, Silvia A1 - Rudock, Megan E A1 - Surakka, Ida A1 - de Geus, Eco J C A1 - Alizadeh, Behrooz Z A1 - Guralnik, Jack A1 - Shuldiner, Alan A1 - Tanaka, Toshiko A1 - Zee, Robert Y L A1 - Schnabel, Renate B A1 - Nambi, Vijay A1 - Kavousi, Maryam A1 - Ripatti, Samuli A1 - Nauck, Matthias A1 - Smith, Nicholas L A1 - Smith, Albert V A1 - Sundvall, Jouko A1 - Scheet, Paul A1 - Liu, Yongmei A1 - Ruokonen, Aimo A1 - Rose, Lynda M A1 - Larson, Martin G A1 - Hoogeveen, Ron C A1 - Freimer, Nelson B A1 - Teumer, Alexander A1 - Tracy, Russell P A1 - Launer, Lenore J A1 - Buring, Julie E A1 - Yamamoto, Jennifer F A1 - Folsom, Aaron R A1 - Sijbrands, Eric J G A1 - Pankow, James A1 - Elliott, Paul A1 - Keaney, John F A1 - Sun, Wei A1 - Sarin, Antti-Pekka A1 - Fontes, João D A1 - Badola, Sunita A1 - Astor, Brad C A1 - Hofman, Albert A1 - Pouta, Anneli A1 - Werdan, Karl A1 - Greiser, Karin H A1 - Kuss, Oliver A1 - Meyer zu Schwabedissen, Henriette E A1 - Thiery, Joachim A1 - Jamshidi, Yalda A1 - Nolte, Ilja M A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Völzke, Henry A1 - Parker, Alexander N A1 - Aspelund, Thor A1 - Bates, David A1 - Young, Lauren A1 - Tsui, Kim A1 - Siscovick, David S A1 - Guo, Xiuqing A1 - Rotter, Jerome I A1 - Uda, Manuela A1 - Schlessinger, David A1 - Rudan, Igor A1 - Hicks, Andrew A A1 - Penninx, Brenda W A1 - Thorand, Barbara A1 - Gieger, Christian A1 - Coresh, Joe A1 - Willemsen, Gonneke A1 - Harris, Tamara B A1 - Uitterlinden, André G A1 - Jarvelin, Marjo-Riitta A1 - Rice, Kenneth A1 - Radke, Dörte A1 - Salomaa, Veikko A1 - Willems van Dijk, Ko A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Ferrucci, Luigi A1 - Gibson, Quince D A1 - Bandinelli, Stefania A1 - Snieder, Harold A1 - Boomsma, Dorret I A1 - Xiao, Xiangjun A1 - Campbell, Harry A1 - Hayward, Caroline A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Peltonen, Leena A1 - Psaty, Bruce M A1 - Gudnason, Vilmundur A1 - Ridker, Paul M A1 - Homuth, Georg A1 - Koenig, Wolfgang A1 - Ballantyne, Christie M A1 - Witteman, Jacqueline C M A1 - Benjamin, Emelia J A1 - Perola, Markus A1 - Chasman, Daniel I KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Vasculitis AB -

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels.

METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease.

CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

VL - 123 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21300955?dopt=Abstract ER - TY - JOUR T1 - Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies. JF - Lancet Neurol Y1 - 2012 A1 - Traylor, Matthew A1 - Farrall, Martin A1 - Holliday, Elizabeth G A1 - Sudlow, Cathie A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Fornage, Myriam A1 - Ikram, M Arfan A1 - Malik, Rainer A1 - Bevan, Steve A1 - Thorsteinsdottir, Unnur A1 - Nalls, Mike A A1 - Longstreth, Wt A1 - Wiggins, Kerri L A1 - Yadav, Sunaina A1 - Parati, Eugenio A A1 - DeStefano, Anita L A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Khan, Muhammad Saleem A1 - Reiner, Alex P A1 - Helgadottir, Anna A1 - Achterberg, Sefanja A1 - Fernandez-Cadenas, Israel A1 - Abboud, Sherine A1 - Schmidt, Reinhold A1 - Walters, Matthew A1 - Chen, Wei-Min A1 - Ringelstein, E Bernd A1 - O'Donnell, Martin A1 - Ho, Weang Kee A1 - Pera, Joanna A1 - Lemmens, Robin A1 - Norrving, Bo A1 - Higgins, Peter A1 - Benn, Marianne A1 - Sale, Michele A1 - Kuhlenbäumer, Gregor A1 - Doney, Alexander S F A1 - Vicente, Astrid M A1 - Delavaran, Hossein A1 - Algra, Ale A1 - Davies, Gail A1 - Oliveira, Sofia A A1 - Palmer, Colin N A A1 - Deary, Ian A1 - Schmidt, Helena A1 - Pandolfo, Massimo A1 - Montaner, Joan A1 - Carty, Cara A1 - de Bakker, Paul I W A1 - Kostulas, Konstantinos A1 - Ferro, Jose M A1 - van Zuydam, Natalie R A1 - Valdimarsson, Einar A1 - Nordestgaard, Børge G A1 - Lindgren, Arne A1 - Thijs, Vincent A1 - Slowik, Agnieszka A1 - Saleheen, Danish A1 - Paré, Guillaume A1 - Berger, Klaus A1 - Thorleifsson, Gudmar A1 - Hofman, Albert A1 - Mosley, Thomas H A1 - Mitchell, Braxton D A1 - Furie, Karen A1 - Clarke, Robert A1 - Levi, Christopher A1 - Seshadri, Sudha A1 - Gschwendtner, Andreas A1 - Boncoraglio, Giorgio B A1 - Sharma, Pankaj A1 - Bis, Joshua C A1 - Gretarsdottir, Solveig A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Stefansson, Kari A1 - Dichgans, Martin A1 - Markus, Hugh S KW - Brain Ischemia KW - Databases, Genetic KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Risk Factors KW - Stroke AB -

BACKGROUND: Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.

METHODS: We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.

FINDINGS: We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10(-16)) and ZFHX3 (p=2·28×10(-8)), and for large-vessel stroke at a 9p21 locus (p=3·32×10(-5)) and HDAC9 (p=2·03×10(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10(-6). However, we were unable to replicate any of these novel associations in the replication cohort.

INTERPRETATION: Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.

FUNDING: Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).

VL - 11 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23041239?dopt=Abstract ER - TY - JOUR T1 - Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. JF - Nat Genet Y1 - 2012 A1 - Stolk, Lisette A1 - Perry, John R B A1 - Chasman, Daniel I A1 - He, Chunyan A1 - Mangino, Massimo A1 - Sulem, Patrick A1 - Barbalic, Maja A1 - Broer, Linda A1 - Byrne, Enda M A1 - Ernst, Florian A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gudbjartsson, Daniel F A1 - Hottenga, Jouke-Jan A1 - Kraft, Peter A1 - McArdle, Patrick F A1 - Porcu, Eleonora A1 - Shin, So-Youn A1 - Smith, Albert V A1 - van Wingerden, Sophie A1 - Zhai, Guangju A1 - Zhuang, Wei V A1 - Albrecht, Eva A1 - Alizadeh, Behrooz Z A1 - Aspelund, Thor A1 - Bandinelli, Stefania A1 - Lauc, Lovorka Barac A1 - Beckmann, Jacques S A1 - Boban, Mladen A1 - Boerwinkle, Eric A1 - Broekmans, Frank J A1 - Burri, Andrea A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chen, Constance A1 - Cornelis, Marilyn C A1 - Corre, Tanguy A1 - Coviello, Andrea D A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Faire, Ulf A1 - de Geus, Eco J C A1 - Deary, Ian J A1 - Dedoussis, George V Z A1 - Deloukas, Panagiotis A1 - Ebrahim, Shah A1 - Eiriksdottir, Gudny A1 - Emilsson, Valur A1 - Eriksson, Johan G A1 - Fauser, Bart C J M A1 - Ferreli, Liana A1 - Ferrucci, Luigi A1 - Fischer, Krista A1 - Folsom, Aaron R A1 - Garcia, Melissa E A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Glazer, Nicole A1 - Grobbee, Diederick E A1 - Hall, Per A1 - Haller, Toomas A1 - Hankinson, Susan E A1 - Hass, Merli A1 - Hayward, Caroline A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Ingelsson, Erik A1 - Janssens, A Cecile J W A1 - Johnson, Andrew D A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Keyzer, Jules A1 - Kiel, Douglas P A1 - Kolcic, Ivana A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Lai, Sandra A1 - Laisk, Triin A1 - Laven, Joop S E A1 - Lawlor, Debbie A A1 - Liu, Jianjun A1 - Lopez, Lorna M A1 - Louwers, Yvonne V A1 - Magnusson, Patrik K E A1 - Marongiu, Mara A1 - Martin, Nicholas G A1 - Klaric, Irena Martinovic A1 - Masciullo, Corrado A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Melzer, David A1 - Mooser, Vincent A1 - Navarro, Pau A1 - Newman, Anne B A1 - Nyholt, Dale R A1 - Onland-Moret, N Charlotte A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Parker, Alex N A1 - Pedersen, Nancy L A1 - Peeters, Petra H M A1 - Pistis, Giorgio A1 - Plump, Andrew S A1 - Polasek, Ozren A1 - Pop, Victor J M A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Rehnberg, Emil A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Sala, Cinzia A1 - Salumets, Andres A1 - Scuteri, Angelo A1 - Singleton, Andrew A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Soranzo, Nicole A1 - Stacey, Simon N A1 - Starr, John M A1 - Stathopoulou, Maria G A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Styrkarsdottir, Unnur A1 - Sun, Yan V A1 - Tenesa, Albert A1 - Thorand, Barbara A1 - Toniolo, Daniela A1 - Tryggvadottir, Laufey A1 - Tsui, Kim A1 - Ulivi, Sheila A1 - van Dam, Rob M A1 - van der Schouw, Yvonne T A1 - van Gils, Carla H A1 - van Nierop, Peter A1 - Vink, Jacqueline M A1 - Visscher, Peter M A1 - Voorhuis, Marlies A1 - Waeber, Gérard A1 - Wallaschofski, Henri A1 - Wichmann, H Erich A1 - Widen, Elisabeth A1 - Wijnands-van Gent, Colette J M A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Zillikens, M Carola A1 - Zygmunt, Marek A1 - Arnold, Alice M A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Demerath, Ellen W A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hu, Frank B A1 - Hunter, David J A1 - Launer, Lenore J A1 - Metspalu, Andres A1 - Montgomery, Grant W A1 - Oostra, Ben A A1 - Ridker, Paul M A1 - Sanna, Serena A1 - Schlessinger, David A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - Uda, Manuela A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Völzke, Henry A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Visser, Jenny A A1 - Lunetta, Kathryn L KW - Age Factors KW - DNA Helicases KW - DNA Polymerase gamma KW - DNA Primase KW - DNA Repair KW - DNA Repair Enzymes KW - DNA-Directed DNA Polymerase KW - European Continental Ancestry Group KW - Exodeoxyribonucleases KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Immunity KW - Menopause KW - Polymorphism, Single Nucleotide KW - Proteins AB -

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

VL - 44 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22267201?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio AB -

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease. JF - Am J Clin Nutr Y1 - 2013 A1 - van Meurs, Joyce B J A1 - Paré, Guillaume A1 - Schwartz, Stephen M A1 - Hazra, Aditi A1 - Tanaka, Toshiko A1 - Vermeulen, Sita H A1 - Cotlarciuc, Ioana A1 - Yuan, Xin A1 - Mälarstig, Anders A1 - Bandinelli, Stefania A1 - Bis, Joshua C A1 - Blom, Henk A1 - Brown, Morris J A1 - Chen, Constance A1 - Chen, Yii-Der A1 - Clarke, Robert J A1 - Dehghan, Abbas A1 - Erdmann, Jeanette A1 - Ferrucci, Luigi A1 - Hamsten, Anders A1 - Hofman, Albert A1 - Hunter, David J A1 - Goel, Anuj A1 - Johnson, Andrew D A1 - Kathiresan, Sekar A1 - Kampman, Ellen A1 - Kiel, Douglas P A1 - Kiemeney, Lambertus A L M A1 - Chambers, John C A1 - Kraft, Peter A1 - Lindemans, Jan A1 - McKnight, Barbara A1 - Nelson, Christopher P A1 - O'Donnell, Christopher J A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Seedorf, Udo A1 - Siscovick, David S A1 - Schunkert, Heribert A1 - Selhub, Jacob A1 - Ueland, Per M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Waterworth, Dawn M A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - den Heijer, Martin A1 - Jacques, Paul A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Rader, Dan J A1 - Reilly, Muredach P A1 - Mooser, Vincent A1 - Chasman, Daniel I A1 - Samani, Nilesh J A1 - Ahmadi, Kourosh R KW - Coronary Artery Disease KW - Genes KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genotype KW - Homocysteine KW - Humans KW - Polymorphism, Genetic KW - Risk Factors AB -

BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD.

OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD.

DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(⁻⁸) were tested for association with CAD in 31,400 cases and 92,927 controls.

RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 × 10⁻⁹), SLC17A3 (1.0 × 10⁻⁸), GTPB10 (1.7 × 10⁻⁸), CUBN (7.5 × 10⁻¹⁰), HNF1A (1.2 × 10⁻¹²)), and FUT2 (6.6 × 10⁻⁹), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-μmol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 × 10⁻³⁶). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49).

CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

VL - 98 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23824729?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. JF - Genet Epidemiol Y1 - 2013 A1 - Tang, Weihong A1 - Teichert, Martina A1 - Chasman, Daniel I A1 - Heit, John A A1 - Morange, Pierre-Emmanuel A1 - Li, Guo A1 - Pankratz, Nathan A1 - Leebeek, Frank W A1 - Paré, Guillaume A1 - de Andrade, Mariza A1 - Tzourio, Christophe A1 - Psaty, Bruce M A1 - Basu, Saonli A1 - Ruiter, Rikje A1 - Rose, Lynda A1 - Armasu, Sebastian M A1 - Lumley, Thomas A1 - Heckbert, Susan R A1 - Uitterlinden, André G A1 - Lathrop, Mark A1 - Rice, Kenneth M A1 - Cushman, Mary A1 - Hofman, Albert A1 - Lambert, Jean-Charles A1 - Glazer, Nicole L A1 - Pankow, James S A1 - Witteman, Jacqueline C A1 - Amouyel, Philippe A1 - Bis, Joshua C A1 - Bovill, Edwin G A1 - Kong, Xiaoxiao A1 - Tracy, Russell P A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Trégouët, David-Alexandre A1 - Loth, Daan W A1 - Stricker, Bruno H Ch A1 - Ridker, Paul M A1 - Folsom, Aaron R A1 - Smith, Nicholas L KW - Aged KW - Aging KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - Venous Thromboembolism AB -

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

VL - 37 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23650146?dopt=Abstract ER - TY - JOUR T1 - Effect of genetic variants associated with plasma homocysteine levels on stroke risk. JF - Stroke Y1 - 2014 A1 - Cotlarciuc, Ioana A1 - Malik, Rainer A1 - Holliday, Elizabeth G A1 - Ahmadi, Kourosh R A1 - Paré, Guillaume A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Hasan, Nazeeha A1 - Rinne, Paul E A1 - Ikram, M Arfan A1 - Markus, Hugh S A1 - Rosand, Jonathan A1 - Mitchell, Braxton D A1 - Kittner, Steven J A1 - Meschia, James F A1 - van Meurs, Joyce B J A1 - Uitterlinden, André G A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Sharma, Pankaj KW - Brain Ischemia KW - Cohort Studies KW - Europe KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome KW - Homocysteine KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk KW - Stroke AB -

BACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.

METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.

RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.

CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.

VL - 45 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24846872?dopt=Abstract ER - TY - JOUR T1 - Genetic Interactions with Age, Sex, Body Mass Index, and Hypertension in Relation to Atrial Fibrillation: The AFGen Consortium. JF - Sci Rep Y1 - 2017 A1 - Weng, Lu-Chen A1 - Lunetta, Kathryn L A1 - Müller-Nurasyid, Martina A1 - Smith, Albert Vernon A1 - Thériault, Sébastien A1 - Weeke, Peter E A1 - Barnard, John A1 - Bis, Joshua C A1 - Lyytikäinen, Leo-Pekka A1 - Kleber, Marcus E A1 - Martinsson, Andreas A1 - Lin, Henry J A1 - Rienstra, Michiel A1 - Trompet, Stella A1 - Krijthe, Bouwe P A1 - Dörr, Marcus A1 - Klarin, Derek A1 - Chasman, Daniel I A1 - Sinner, Moritz F A1 - Waldenberger, Melanie A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Alonso, Alvaro A1 - Paré, Guillaume A1 - Teixeira, Pedro L A1 - Denny, Joshua C A1 - Shoemaker, M Benjamin A1 - Van Wagoner, David R A1 - Smith, Jonathan D A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Taylor, Kent D A1 - Kähönen, Mika A1 - Nikus, Kjell A1 - Delgado, Graciela E A1 - Melander, Olle A1 - Engström, Gunnar A1 - Yao, Jie A1 - Guo, Xiuqing A1 - Christophersen, Ingrid E A1 - Ellinor, Patrick T A1 - Geelhoed, Bastiaan A1 - Verweij, Niek A1 - Macfarlane, Peter A1 - Ford, Ian A1 - Heeringa, Jan A1 - Franco, Oscar H A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Teumer, Alexander A1 - Rose, Lynda M A1 - Kääb, Stefan A1 - Gudnason, Vilmundur A1 - Arking, Dan E A1 - Conen, David A1 - Roden, Dan M A1 - Chung, Mina K A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Lehtimäki, Terho A1 - März, Winfried A1 - Smith, J Gustav A1 - Rotter, Jerome I A1 - van der Harst, Pim A1 - Jukema, J Wouter A1 - Stricker, Bruno H A1 - Felix, Stephan B A1 - Albert, Christine M A1 - Lubitz, Steven A AB -

It is unclear whether genetic markers interact with risk factors to influence atrial fibrillation (AF) risk. We performed genome-wide interaction analyses between genetic variants and age, sex, hypertension, and body mass index in the AFGen Consortium. Study-specific results were combined using meta-analysis (88,383 individuals of European descent, including 7,292 with AF). Variants with nominal interaction associations in the discovery analysis were tested for association in four independent studies (131,441 individuals, including 5,722 with AF). In the discovery analysis, the AF risk associated with the minor rs6817105 allele (at the PITX2 locus) was greater among subjects ≤ 65 years of age than among those > 65 years (interaction p-value = 4.0 × 10-5). The interaction p-value exceeded genome-wide significance in combined discovery and replication analyses (interaction p-value = 1.7 × 10-8). We observed one genome-wide significant interaction with body mass index and several suggestive interactions with age, sex, and body mass index in the discovery analysis. However, none was replicated in the independent sample. Our findings suggest that the pathogenesis of AF may differ according to age in individuals of European descent, but we did not observe evidence of statistically significant genetic interactions with sex, body mass index, or hypertension on AF risk.

VL - 7 IS - 1 ER - TY - JOUR T1 - Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation. JF - Nat Genet Y1 - 2017 A1 - Christophersen, Ingrid E A1 - Rienstra, Michiel A1 - Roselli, Carolina A1 - Yin, Xiaoyan A1 - Geelhoed, Bastiaan A1 - Barnard, John A1 - Lin, Honghuang A1 - Arking, Dan E A1 - Smith, Albert V A1 - Albert, Christine M A1 - Chaffin, Mark A1 - Tucker, Nathan R A1 - Li, Molong A1 - Klarin, Derek A1 - Bihlmeyer, Nathan A A1 - Low, Siew-Kee A1 - Weeke, Peter E A1 - Müller-Nurasyid, Martina A1 - Smith, J Gustav A1 - Brody, Jennifer A A1 - Niemeijer, Maartje N A1 - Dörr, Marcus A1 - Trompet, Stella A1 - Huffman, Jennifer A1 - Gustafsson, Stefan A1 - Schurmann, Claudia A1 - Kleber, Marcus E A1 - Lyytikäinen, Leo-Pekka A1 - Seppälä, Ilkka A1 - Malik, Rainer A1 - Horimoto, Andrea R V R A1 - Perez, Marco A1 - Sinisalo, Juha A1 - Aeschbacher, Stefanie A1 - Thériault, Sébastien A1 - Yao, Jie A1 - Radmanesh, Farid A1 - Weiss, Stefan A1 - Teumer, Alexander A1 - Choi, Seung Hoan A1 - Weng, Lu-Chen A1 - Clauss, Sebastian A1 - Deo, Rajat A1 - Rader, Daniel J A1 - Shah, Svati H A1 - Sun, Albert A1 - Hopewell, Jemma C A1 - Debette, Stephanie A1 - Chauhan, Ganesh A1 - Yang, Qiong A1 - Worrall, Bradford B A1 - Paré, Guillaume A1 - Kamatani, Yoichiro A1 - Hagemeijer, Yanick P A1 - Verweij, Niek A1 - Siland, Joylene E A1 - Kubo, Michiaki A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Bis, Joshua C A1 - Perz, Siegfried A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Magnani, Jared W A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Shoemaker, M Benjamin A1 - Padmanabhan, Sandosh A1 - Haessler, Jeffrey A1 - Bartz, Traci M A1 - Waldenberger, Melanie A1 - Lichtner, Peter A1 - Arendt, Marina A1 - Krieger, Jose E A1 - Kähönen, Mika A1 - Risch, Lorenz A1 - Mansur, Alfredo J A1 - Peters, Annette A1 - Smith, Blair H A1 - Lind, Lars A1 - Scott, Stuart A A1 - Lu, Yingchang A1 - Bottinger, Erwin B A1 - Hernesniemi, Jussi A1 - Lindgren, Cecilia M A1 - Wong, Jorge A A1 - Huang, Jie A1 - Eskola, Markku A1 - Morris, Andrew P A1 - Ford, Ian A1 - Reiner, Alex P A1 - Delgado, Graciela A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Sandhu, Roopinder K A1 - Li, Man A1 - Boerwinkle, Eric A1 - Eisele, Lewin A1 - Lannfelt, Lars A1 - Rost, Natalia A1 - Anderson, Christopher D A1 - Taylor, Kent D A1 - Campbell, Archie A1 - Magnusson, Patrik K A1 - Porteous, David A1 - Hocking, Lynne J A1 - Vlachopoulou, Efthymia A1 - Pedersen, Nancy L A1 - Nikus, Kjell A1 - Orho-Melander, Marju A1 - Hamsten, Anders A1 - Heeringa, Jan A1 - Denny, Joshua C A1 - Kriebel, Jennifer A1 - Darbar, Dawood A1 - Newton-Cheh, Christopher A1 - Shaffer, Christian A1 - Macfarlane, Peter W A1 - Heilmann-Heimbach, Stefanie A1 - Almgren, Peter A1 - Huang, Paul L A1 - Sotoodehnia, Nona A1 - Soliman, Elsayed Z A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Völker, Uwe A1 - Jöckel, Karl-Heinz A1 - Sinner, Moritz F A1 - Lin, Henry J A1 - Guo, Xiuqing A1 - Dichgans, Martin A1 - Ingelsson, Erik A1 - Kooperberg, Charles A1 - Melander, Olle A1 - Loos, Ruth J F A1 - Laurikka, Jari A1 - Conen, David A1 - Rosand, Jonathan A1 - van der Harst, Pim A1 - Lokki, Marja-Liisa A1 - Kathiresan, Sekar A1 - Pereira, Alexandre A1 - Jukema, J Wouter A1 - Hayward, Caroline A1 - Rotter, Jerome I A1 - März, Winfried A1 - Lehtimäki, Terho A1 - Stricker, Bruno H A1 - Chung, Mina K A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Alonso, Alvaro A1 - Roden, Dan M A1 - Kääb, Stefan A1 - Chasman, Daniel I A1 - Heckbert, Susan R A1 - Benjamin, Emelia J A1 - Tanaka, Toshihiro A1 - Lunetta, Kathryn L A1 - Lubitz, Steven A A1 - Ellinor, Patrick T AB -

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery.

VL - 49 IS - 6 ER - TY - JOUR T1 - Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney. JF - Hypertension Y1 - 2017 A1 - Wain, Louise V A1 - Vaez, Ahmad A1 - Jansen, Rick A1 - Joehanes, Roby A1 - van der Most, Peter J A1 - Erzurumluoglu, A Mesut A1 - O'Reilly, Paul F A1 - Cabrera, Claudia P A1 - Warren, Helen R A1 - Rose, Lynda M A1 - Verwoert, Germaine C A1 - Hottenga, Jouke-Jan A1 - Strawbridge, Rona J A1 - Esko, Tõnu A1 - Arking, Dan E A1 - Hwang, Shih-Jen A1 - Guo, Xiuqing A1 - Kutalik, Zoltán A1 - Trompet, Stella A1 - Shrine, Nick A1 - Teumer, Alexander A1 - Ried, Janina S A1 - Bis, Joshua C A1 - Smith, Albert V A1 - Amin, Najaf A1 - Nolte, Ilja M A1 - Lyytikäinen, Leo-Pekka A1 - Mahajan, Anubha A1 - Wareham, Nicholas J A1 - Hofer, Edith A1 - Joshi, Peter K A1 - Kristiansson, Kati A1 - Traglia, Michela A1 - Havulinna, Aki S A1 - Goel, Anuj A1 - Nalls, Mike A A1 - Sõber, Siim A1 - Vuckovic, Dragana A1 - Luan, Jian'an A1 - del Greco M, Fabiola A1 - Ayers, Kristin L A1 - Marrugat, Jaume A1 - Ruggiero, Daniela A1 - Lopez, Lorna M A1 - Niiranen, Teemu A1 - Enroth, Stefan A1 - Jackson, Anne U A1 - Nelson, Christopher P A1 - Huffman, Jennifer E A1 - Zhang, Weihua A1 - Marten, Jonathan A1 - Gandin, Ilaria A1 - Harris, Sarah E A1 - Zemunik, Tatijana A1 - Lu, Yingchang A1 - Evangelou, Evangelos A1 - Shah, Nabi A1 - de Borst, Martin H A1 - Mangino, Massimo A1 - Prins, Bram P A1 - Campbell, Archie A1 - Li-Gao, Ruifang A1 - Chauhan, Ganesh A1 - Oldmeadow, Christopher A1 - Abecasis, Goncalo A1 - Abedi, Maryam A1 - Barbieri, Caterina M A1 - Barnes, Michael R A1 - Batini, Chiara A1 - Beilby, John A1 - Blake, Tineka A1 - Boehnke, Michael A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brown, Morris A1 - Brumat, Marco A1 - Campbell, Harry A1 - Chambers, John C A1 - Cocca, Massimiliano A1 - Collins, Francis A1 - Connell, John A1 - Cordell, Heather J A1 - Damman, Jeffrey J A1 - Davies, Gail A1 - de Geus, Eco J A1 - de Mutsert, Renée A1 - Deelen, Joris A1 - Demirkale, Yusuf A1 - Doney, Alex S F A1 - Dörr, Marcus A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Frånberg, Mattias A1 - Gao, He A1 - Giedraitis, Vilmantas A1 - Gieger, Christian A1 - Giulianini, Franco A1 - Gow, Alan J A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Holliday, Elizabeth G A1 - Hui, Jennie A1 - Jarvelin, Marjo-Riitta A1 - Johansson, Asa A1 - Johnson, Andrew D A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Khaw, Kay-Tee A1 - Kolcic, Ivana A1 - Koskinen, Seppo A1 - Langenberg, Claudia A1 - Larson, Marty A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Liewald, David C M A1 - Lin, Li A1 - Lind, Lars A1 - Mach, François A1 - Mamasoula, Chrysovalanto A1 - Menni, Cristina A1 - Mifsud, Borbala A1 - Milaneschi, Yuri A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morrison, Alanna C A1 - Munson, Peter J A1 - Nandakumar, Priyanka A1 - Nguyen, Quang Tri A1 - Nutile, Teresa A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Org, Elin A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Paré, Guillaume A1 - Pattie, Alison A1 - Penninx, Brenda W J H A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Ren, Meixia A1 - Rice, Kenneth A1 - Ridker, Paul M A1 - Riese, Harriëtte A1 - Ripatti, Samuli A1 - Robino, Antonietta A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Saba, Yasaman A1 - Saint Pierre, Aude A1 - Sala, Cinzia F A1 - Sarin, Antti-Pekka A1 - Schmidt, Reinhold A1 - Scott, Rodney A1 - Seelen, Marc A A1 - Shields, Denis C A1 - Siscovick, David A1 - Sorice, Rossella A1 - Stanton, Alice A1 - Stott, David J A1 - Sundström, Johan A1 - Swertz, Morris A1 - Taylor, Kent D A1 - Thom, Simon A1 - Tzoulaki, Ioanna A1 - Tzourio, Christophe A1 - Uitterlinden, André G A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wild, Sarah A1 - Willemsen, Gonneke A1 - Wright, Alan F A1 - Yao, Jie A1 - Thériault, Sébastien A1 - Conen, David A1 - Attia, John A1 - Sever, Peter A1 - Debette, Stephanie A1 - Mook-Kanamori, Dennis O A1 - Zeggini, Eleftheria A1 - Spector, Tim D A1 - van der Harst, Pim A1 - Palmer, Colin N A A1 - Vergnaud, Anne-Claire A1 - Loos, Ruth J F A1 - Polasek, Ozren A1 - Starr, John M A1 - Girotto, Giorgia A1 - Hayward, Caroline A1 - Kooner, Jaspal S A1 - Lindgren, Cecila M A1 - Vitart, Veronique A1 - Samani, Nilesh J A1 - Tuomilehto, Jaakko A1 - Gyllensten, Ulf A1 - Knekt, Paul A1 - Deary, Ian J A1 - Ciullo, Marina A1 - Elosua, Roberto A1 - Keavney, Bernard D A1 - Hicks, Andrew A A1 - Scott, Robert A A1 - Gasparini, Paolo A1 - Laan, Maris A1 - Liu, Yongmei A1 - Watkins, Hugh A1 - Hartman, Catharina A A1 - Salomaa, Veikko A1 - Toniolo, Daniela A1 - Perola, Markus A1 - Wilson, James F A1 - Schmidt, Helena A1 - Zhao, Jing Hua A1 - Lehtimäki, Terho A1 - van Duijn, Cornelia M A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Peters, Annette A1 - Rettig, Rainer A1 - James, Alan A1 - Jukema, J Wouter A1 - Strachan, David P A1 - Palmas, Walter A1 - Metspalu, Andres A1 - Ingelsson, Erik A1 - Boomsma, Dorret I A1 - Franco, Oscar H A1 - Bochud, Murielle A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Elliott, Paul A1 - Chasman, Daniel I A1 - Chakravarti, Aravinda A1 - Knight, Joanne A1 - Morris, Andrew P A1 - Levy, Daniel A1 - Tobin, Martin D A1 - Snieder, Harold A1 - Caulfield, Mark J A1 - Ehret, Georg B AB -

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA 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.

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

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

VL - 50 IS - 10 ER - TY - JOUR T1 - Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. JF - Nat Genet Y1 - 2018 A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - den Hoed, Marcel A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Bis, Joshua C A1 - Pastinen, Tomi A1 - Ruusalepp, Arno A1 - Schadt, Eric E A1 - Koplev, Simon A1 - Björkegren, Johan L M A1 - Codoni, Veronica A1 - Civelek, Mete A1 - Smith, Nicholas L A1 - Trégouët, David A A1 - Christophersen, Ingrid E A1 - Roselli, Carolina A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Tai, E Shyong A1 - Kooner, Jaspal S A1 - Kato, Norihiro A1 - He, Jiang A1 - van der Harst, Pim A1 - Elliott, Paul A1 - Chambers, John C A1 - Takeuchi, Fumihiko A1 - Johnson, Andrew D A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Chauhan, Ganesh A1 - Traylor, Matthew A1 - Sargurupremraj, Muralidharan A1 - Okada, Yukinori A1 - Mishra, Aniket A1 - Rutten-Jacobs, Loes A1 - Giese, Anne-Katrin A1 - van der Laan, Sander W A1 - Gretarsdottir, Solveig A1 - Anderson, Christopher D A1 - Chong, Michael A1 - Adams, Hieab H H A1 - Ago, Tetsuro A1 - Almgren, Peter A1 - Amouyel, Philippe A1 - Ay, Hakan A1 - Bartz, Traci M A1 - Benavente, Oscar R A1 - Bevan, Steve A1 - Boncoraglio, Giorgio B A1 - Brown, Robert D A1 - Butterworth, Adam S A1 - Carrera, Caty A1 - Carty, Cara L A1 - Chasman, Daniel I A1 - Chen, Wei-Min A1 - Cole, John W A1 - Correa, Adolfo A1 - Cotlarciuc, Ioana A1 - Cruchaga, Carlos A1 - Danesh, John A1 - de Bakker, Paul I W A1 - DeStefano, Anita L A1 - Hoed, Marcel den A1 - Duan, Qing A1 - Engelter, Stefan T A1 - Falcone, Guido J A1 - Gottesman, Rebecca F A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Haessler, Jeffrey A1 - Harris, Tamara B A1 - Hassan, Ahamad A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Holliday, Elizabeth G A1 - Howard, George A1 - Hsu, Fang-Chi A1 - Hyacinth, Hyacinth I A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Irvin, Marguerite R A1 - Jian, Xueqiu A1 - Jimenez-Conde, Jordi A1 - Johnson, Julie A A1 - Jukema, J Wouter A1 - Kanai, Masahiro A1 - Keene, Keith L A1 - Kissela, Brett M A1 - Kleindorfer, Dawn O A1 - Kooperberg, Charles A1 - Kubo, Michiaki A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lee, Jin-Moo A1 - Lemmens, Robin A1 - Leys, Didier A1 - Lewis, Cathryn M A1 - Lin, Wei-Yu A1 - Lindgren, Arne G A1 - Lorentzen, Erik A1 - Magnusson, Patrik K A1 - Maguire, Jane A1 - Manichaikul, Ani A1 - McArdle, Patrick F A1 - Meschia, James F A1 - Mitchell, Braxton D A1 - Mosley, Thomas H A1 - Nalls, Michael A A1 - Ninomiya, Toshiharu A1 - O'Donnell, Martin J A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Rannikmae, Kristiina A1 - Reiner, Alexander P A1 - Rexrode, Kathryn M A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rost, Natalia S A1 - Rothwell, Peter M A1 - Rotter, Jerome I A1 - Rundek, Tatjana A1 - Sacco, Ralph L A1 - Sakaue, Saori A1 - Sale, Michèle M A1 - Salomaa, Veikko A1 - Sapkota, Bishwa R A1 - Schmidt, Reinhold A1 - Schmidt, Carsten O A1 - Schminke, Ulf A1 - Sharma, Pankaj A1 - Slowik, Agnieszka A1 - Sudlow, Cathie L M A1 - Tanislav, Christian A1 - Tatlisumak, Turgut A1 - Taylor, Kent D A1 - Thijs, Vincent N S A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tiedt, Steffen A1 - Trompet, Stella A1 - Tzourio, Christophe A1 - van Duijn, Cornelia M A1 - Walters, Matthew A1 - Wareham, Nicholas J A1 - Wassertheil-Smoller, Sylvia A1 - Wilson, James G A1 - Wiggins, Kerri L A1 - Yang, Qiong A1 - Yusuf, Salim A1 - Amin, Najaf A1 - Aparicio, Hugo S A1 - Arnett, Donna K A1 - Attia, John A1 - Beiser, Alexa S A1 - Berr, Claudine A1 - Buring, Julie E A1 - Bustamante, Mariana A1 - Caso, Valeria A1 - Cheng, Yu-Ching A1 - Choi, Seung Hoan A1 - Chowhan, Ayesha A1 - Cullell, Natalia A1 - Dartigues, Jean-François A1 - Delavaran, Hossein A1 - Delgado, Pilar A1 - Dörr, Marcus A1 - Engström, Gunnar A1 - Ford, Ian A1 - Gurpreet, Wander S A1 - Hamsten, Anders A1 - Heitsch, Laura A1 - Hozawa, Atsushi A1 - Ibanez, Laura A1 - Ilinca, Andreea A1 - Ingelsson, Martin A1 - Iwasaki, Motoki A1 - Jackson, Rebecca D A1 - Jood, Katarina A1 - Jousilahti, Pekka A1 - Kaffashian, Sara A1 - Kalra, Lalit A1 - Kamouchi, Masahiro A1 - Kitazono, Takanari A1 - Kjartansson, Olafur A1 - Kloss, Manja A1 - Koudstaal, Peter J A1 - Krupinski, Jerzy A1 - Labovitz, Daniel L A1 - Laurie, Cathy C A1 - Levi, Christopher R A1 - Li, Linxin A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lioutas, Vasileios A1 - Liu, Yong Mei A1 - Lopez, Oscar L A1 - Makoto, Hirata A1 - Martinez-Majander, Nicolas A1 - Matsuda, Koichi A1 - Minegishi, Naoko A1 - Montaner, Joan A1 - Morris, Andrew P A1 - Muiño, Elena A1 - Müller-Nurasyid, Martina A1 - Norrving, Bo A1 - Ogishima, Soichi A1 - Parati, Eugenio A A1 - Peddareddygari, Leema Reddy A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Perola, Markus A1 - Pezzini, Alessandro A1 - Pileggi, Silvana A1 - Rabionet, Raquel A1 - Riba-Llena, Iolanda A1 - Ribasés, Marta A1 - Romero, Jose R A1 - Roquer, Jaume A1 - Rudd, Anthony G A1 - Sarin, Antti-Pekka A1 - Sarju, Ralhan A1 - Sarnowski, Chloe A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Satoh, Mamoru A1 - Sattar, Naveed A1 - Sawada, Norie A1 - Sibolt, Gerli A1 - Sigurdsson, Ásgeir A1 - Smith, Albert A1 - Sobue, Kenji A1 - Soriano-Tárraga, Carolina A1 - Stanne, Tara A1 - Stine, O Colin A1 - Stott, David J A1 - Strauch, Konstantin A1 - Takai, Takako A1 - Tanaka, Hideo A1 - Tanno, Kozo A1 - Teumer, Alexander A1 - Tomppo, Liisa A1 - Torres-Aguila, Nuria P A1 - Touze, Emmanuel A1 - Tsugane, Shoichiro A1 - Uitterlinden, André G A1 - Valdimarsson, Einar M A1 - van der Lee, Sven J A1 - Völzke, Henry A1 - Wakai, Kenji A1 - Weir, David A1 - Williams, Stephen R A1 - Wolfe, Charles D A A1 - Wong, Quenna A1 - Xu, Huichun A1 - Yamaji, Taiki A1 - Sanghera, Dharambir K A1 - Melander, Olle A1 - Jern, Christina A1 - Strbian, Daniel A1 - Fernandez-Cadenas, Israel A1 - Longstreth, W T A1 - Rolfs, Arndt A1 - Hata, Jun A1 - Woo, Daniel A1 - Rosand, Jonathan A1 - Paré, Guillaume A1 - Hopewell, Jemma C A1 - Saleheen, Danish A1 - Stefansson, Kari A1 - Worrall, Bradford B A1 - Kittner, Steven J A1 - Seshadri, Sudha A1 - Fornage, Myriam A1 - Markus, Hugh S A1 - Howson, Joanna M M A1 - Kamatani, Yoichiro A1 - Debette, Stephanie A1 - Dichgans, Martin AB -

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

VL - 50 IS - 4 ER - TY - JOUR T1 - Multi-ethnic genome-wide association study for atrial fibrillation. JF - Nat Genet Y1 - 2018 A1 - Roselli, Carolina A1 - Chaffin, Mark D A1 - Weng, Lu-Chen A1 - Aeschbacher, Stefanie A1 - Ahlberg, Gustav A1 - Albert, Christine M A1 - Almgren, Peter A1 - Alonso, Alvaro A1 - Anderson, Christopher D A1 - Aragam, Krishna G A1 - Arking, Dan E A1 - Barnard, John A1 - Bartz, Traci M A1 - Benjamin, Emelia J A1 - Bihlmeyer, Nathan A A1 - Bis, Joshua C A1 - Bloom, Heather L A1 - Boerwinkle, Eric A1 - Bottinger, Erwin B A1 - Brody, Jennifer A A1 - Calkins, Hugh A1 - Campbell, Archie A1 - Cappola, Thomas P A1 - Carlquist, John A1 - Chasman, Daniel I A1 - Chen, Lin Y A1 - Chen, Yii-Der Ida A1 - Choi, Eue-Keun A1 - Choi, Seung Hoan A1 - Christophersen, Ingrid E A1 - Chung, Mina K A1 - Cole, John W A1 - Conen, David A1 - Cook, James A1 - Crijns, Harry J A1 - Cutler, Michael J A1 - Damrauer, Scott M A1 - Daniels, Brian R A1 - Darbar, Dawood A1 - Delgado, Graciela A1 - Denny, Joshua C A1 - Dichgans, Martin A1 - Dörr, Marcus A1 - Dudink, Elton A A1 - Dudley, Samuel C A1 - Esa, Nada A1 - Esko, Tõnu A1 - Eskola, Markku A1 - Fatkin, Diane A1 - Felix, Stephan B A1 - Ford, Ian A1 - Franco, Oscar H A1 - Geelhoed, Bastiaan A1 - Grewal, Raji P A1 - Gudnason, Vilmundur A1 - Guo, Xiuqing A1 - Gupta, Namrata A1 - Gustafsson, Stefan A1 - Gutmann, Rebecca A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heckbert, Susan R A1 - Hernesniemi, Jussi A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Horimoto, Andrea R V R A1 - Huang, Jie A1 - Huang, Paul L A1 - Huffman, Jennifer A1 - Ingelsson, Erik A1 - Ipek, Esra Gucuk A1 - Ito, Kaoru A1 - Jimenez-Conde, Jordi A1 - Johnson, Renee A1 - Jukema, J Wouter A1 - Kääb, Stefan A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kane, John P A1 - Kastrati, Adnan A1 - Kathiresan, Sekar A1 - Katschnig-Winter, Petra A1 - Kavousi, Maryam A1 - Kessler, Thorsten A1 - Kietselaer, Bas L A1 - Kirchhof, Paulus A1 - Kleber, Marcus E A1 - Knight, Stacey A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Launer, Lenore J A1 - Laurikka, Jari A1 - Lehtimäki, Terho A1 - Leineweber, Kirsten A1 - Lemaitre, Rozenn N A1 - Li, Man A1 - Lim, Hong Euy A1 - Lin, Henry J A1 - Lin, Honghuang A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Lokki, Marja-Liisa A1 - London, Barry A1 - Loos, Ruth J F A1 - Low, Siew-Kee A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Macfarlane, Peter W A1 - Magnusson, Patrik K A1 - Mahajan, Anubha A1 - Malik, Rainer A1 - Mansur, Alfredo J A1 - Marcus, Gregory M A1 - Margolin, Lauren A1 - Margulies, Kenneth B A1 - März, Winfried A1 - McManus, David D A1 - Melander, Olle A1 - Mohanty, Sanghamitra A1 - Montgomery, Jay A A1 - Morley, Michael P A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Natale, Andrea A1 - Nazarian, Saman A1 - Neumann, Benjamin A1 - Newton-Cheh, Christopher A1 - Niemeijer, Maartje N A1 - Nikus, Kjell A1 - Nilsson, Peter A1 - Noordam, Raymond A1 - Oellers, Heidi A1 - Olesen, Morten S A1 - Orho-Melander, Marju A1 - Padmanabhan, Sandosh A1 - Pak, Hui-Nam A1 - Paré, Guillaume A1 - Pedersen, Nancy L A1 - Pera, Joanna A1 - Pereira, Alexandre A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pulit, Sara L A1 - Pullinger, Clive R A1 - Rader, Daniel J A1 - Refsgaard, Lena A1 - Ribasés, Marta A1 - Ridker, Paul M A1 - Rienstra, Michiel A1 - Risch, Lorenz A1 - Roden, Dan M A1 - Rosand, Jonathan A1 - Rosenberg, Michael A A1 - Rost, Natalia A1 - Rotter, Jerome I A1 - Saba, Samir A1 - Sandhu, Roopinder K A1 - Schnabel, Renate B A1 - Schramm, Katharina A1 - Schunkert, Heribert A1 - Schurman, Claudia A1 - Scott, Stuart A A1 - Seppälä, Ilkka A1 - Shaffer, Christian A1 - Shah, Svati A1 - Shalaby, Alaa A A1 - Shim, Jaemin A1 - Shoemaker, M Benjamin A1 - Siland, Joylene E A1 - Sinisalo, Juha A1 - Sinner, Moritz F A1 - Slowik, Agnieszka A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, J Gustav A1 - Smith, Jonathan D A1 - Smith, Nicholas L A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stricker, Bruno H A1 - Sun, Albert A1 - Sun, Han A1 - Svendsen, Jesper H A1 - Tanaka, Toshihiro A1 - Tanriverdi, Kahraman A1 - Taylor, Kent D A1 - Teder-Laving, Maris A1 - Teumer, Alexander A1 - Thériault, Sébastien A1 - Trompet, Stella A1 - Tucker, Nathan R A1 - Tveit, Arnljot A1 - Uitterlinden, André G A1 - van der Harst, Pim A1 - Van Gelder, Isabelle C A1 - Van Wagoner, David R A1 - Verweij, Niek A1 - Vlachopoulou, Efthymia A1 - Völker, Uwe A1 - Wang, Biqi A1 - Weeke, Peter E A1 - Weijs, Bob A1 - Weiss, Raul A1 - Weiss, Stefan A1 - Wells, Quinn S A1 - Wiggins, Kerri L A1 - Wong, Jorge A A1 - Woo, Daniel A1 - Worrall, Bradford B A1 - Yang, Pil-Sung A1 - Yao, Jie A1 - Yoneda, Zachary T A1 - Zeller, Tanja A1 - Zeng, Lingyao A1 - Lubitz, Steven A A1 - Lunetta, Kathryn L A1 - Ellinor, Patrick T AB -

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

VL - 50 IS - 9 ER - TY - JOUR T1 - Epigenetic Age and the Risk of Incident Atrial Fibrillation. JF - Circulation Y1 - 2021 A1 - Roberts, Jason D A1 - Vittinghoff, Eric A1 - Lu, Ake T A1 - Alonso, Alvaro A1 - Wang, Biqi A1 - Sitlani, Colleen M A1 - Mohammadi-Shemirani, Pedrum A1 - Fornage, Myriam A1 - Kornej, Jelena A1 - Brody, Jennifer A A1 - Arking, Dan E A1 - Lin, Honghuang A1 - Heckbert, Susan R A1 - Prokic, Ivana A1 - Ghanbari, Mohsen A1 - Skanes, Allan C A1 - Bartz, Traci M A1 - Perez, Marco V A1 - Taylor, Kent D A1 - Lubitz, Steven A A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Pankow, James S A1 - Paré, Guillaume A1 - Sotoodehnia, Nona A1 - Benjamin, Emelia J A1 - Horvath, Steve A1 - Marcus, Gregory M KW - Aged KW - Aging KW - Atrial Fibrillation KW - DNA Methylation KW - Epigenesis, Genetic KW - Epigenomics KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Cardiovascular KW - Models, Genetic AB -

BACKGROUND: The most prominent risk factor for atrial fibrillation (AF) is chronological age; however, underlying mechanisms are unexplained. Algorithms using epigenetic modifications to the human genome effectively predict chronological age. Chronological and epigenetic predicted ages may diverge in a phenomenon referred to as epigenetic age acceleration (EAA), which may reflect accelerated biological aging. We sought to evaluate for associations between epigenetic age measures and incident AF.

METHODS: Measures for 4 epigenetic clocks (Horvath, Hannum, DNA methylation [DNAm] PhenoAge, and DNAm GrimAge) and an epigenetic predictor of PAI-1 (plasminogen activator inhibitor-1) levels (ie, DNAm PAI-1) were determined for study participants from 3 population-based cohort studies. Cox models evaluated for associations with incident AF and results were combined via random-effects meta-analyses. Two-sample summary-level Mendelian randomization analyses evaluated for associations between genetic instruments of the EAA measures and AF.

RESULTS: Among 5600 participants (mean age, 65.5 years; female, 60.1%; Black, 50.7%), there were 905 incident AF cases during a mean follow-up of 12.9 years. Unadjusted analyses revealed all 4 epigenetic clocks and the DNAm PAI-1 predictor were associated with statistically significant higher hazards of incident AF, though the magnitudes of their point estimates were smaller relative to the associations observed for chronological age. The pooled EAA estimates for each epigenetic measure, with the exception of Horvath EAA, were associated with incident AF in models adjusted for chronological age, race, sex, and smoking variables. After multivariable adjustment for additional known AF risk factors that could also potentially function as mediators, pooled EAA measures for 2 clocks remained statistically significant. Five-year increases in EAA measures for DNAm GrimAge and DNAm PhenoAge were associated with 19% (adjusted hazard ratio [HR], 1.19 [95% CI, 1.09-1.31]; <0.01) and 15% (adjusted HR, 1.15 [95% CI, 1.05-1.25]; <0.01) higher hazards of incident AF, respectively. Mendelian randomization analyses for the 5 EAA measures did not reveal statistically significant associations with AF.

CONCLUSIONS: Our study identified adjusted associations between EAA measures and incident AF, suggesting that biological aging plays an important role independent of chronological age, though a potential underlying causal relationship remains unclear. These aging processes may be modifiable and not constrained by the immutable factor of time.

VL - 144 IS - 24 ER - TY - JOUR T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. JF - Nat Genet Y1 - 2022 A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Zhang, Weihua A1 - Ng, Maggie C Y A1 - Petty, Lauren E A1 - Kitajima, Hidetoshi A1 - Yu, Grace Z A1 - Rüeger, Sina A1 - Speidel, Leo A1 - Kim, Young Jin A1 - Horikoshi, Momoko A1 - Mercader, Josep M A1 - Taliun, Daniel A1 - Moon, Sanghoon A1 - Kwak, Soo-Heon A1 - Robertson, Neil R A1 - Rayner, Nigel W A1 - Loh, Marie A1 - Kim, Bong-Jo A1 - Chiou, Joshua A1 - Miguel-Escalada, Irene A1 - Della Briotta Parolo, Pietro A1 - Lin, Kuang A1 - Bragg, Fiona A1 - Preuss, Michael H A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Guo, Xiuqing A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Scott, Robert A A1 - Lee, Jung-Jin A1 - Huerta-Chagoya, Alicia A1 - Graff, Mariaelisa A1 - Chai, Jin-Fang A1 - Parra, Esteban J A1 - Yao, Jie A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Steinthorsdottir, Valgerdur A1 - Cook, James P A1 - Kals, Mart A1 - Grarup, Niels A1 - Schmidt, Ellen M A1 - Pan, Ian A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Ahmad, Meraj A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Lecoeur, Cécile A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Jensen, Richard A A1 - Tajuddin, Salman A1 - Kabagambe, Edmond K A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Flanagan, Jack A1 - Abaitua, Fernando A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Akiyama, Masato A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bian, Zheng A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Brummett, Chad M A1 - Buchanan, Thomas A A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Fuchsberger, Christian A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Goodarzi, Mark O A1 - Gordon-Larsen, Penny A1 - Gorkin, David A1 - Gross, Myron A1 - Guo, Yu A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Kamatani, Yoichiro A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kohara, Katsuhiko A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lyssenko, Valeriya A1 - Mamakou, Vasiliki A1 - Mani, K Radha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nadkarni, Girish N A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Nongmaithem, Suraj S A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Preissl, Sebastian A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Kathryn A1 - Sabanayagam, Charumathi A1 - Sander, Maike A1 - Sandow, Kevin A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Schurmann, Claudia A1 - Shahriar, Mohammad A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shriner, Daniel A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Suzuki, Ken A1 - Takahashi, Atsushi A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Torres, Jason M A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Vujkovic, Marijana A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Whitsel, Eric A A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamauchi, Toshimasa A1 - Yengo, Loic A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Hanis, Craig L A1 - Peyser, Patricia A A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Zeggini, Eleftheria A1 - Yokota, Mitsuhiro A1 - Rich, Stephen S A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Engert, James C A1 - Chen, Yii-Der Ida A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Kardia, Sharon L R A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Groop, Leif A1 - Mook-Kanamori, Dennis O A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Bottinger, Erwin P A1 - Dehghan, Abbas A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Palmer, Colin N A A1 - Liu, Simin A1 - Abecasis, Goncalo A1 - Kooner, Jaspal S A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A A1 - Florez, Jose C A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Mägi, Reedik A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Maeda, Shiro A1 - Kadowaki, Takashi A1 - Lee, Juyoung A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Myers, Simon R A1 - Ferrer, Jorge A1 - Gaulton, Kyle J A1 - Meigs, James B A1 - Mohlke, Karen L A1 - Gloyn, Anna L A1 - Bowden, Donald W A1 - Below, Jennifer E A1 - Chambers, John C A1 - Sim, Xueling A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - McCarthy, Mark I A1 - Morris, Andrew P KW - Diabetes Mellitus, Type 2 KW - Ethnicity KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

VL - 54 IS - 5 ER - TY - JOUR T1 - Stroke genetics informs drug discovery and risk prediction across ancestries. JF - Nature Y1 - 2022 A1 - Mishra, Aniket A1 - Malik, Rainer A1 - Hachiya, Tsuyoshi A1 - Jürgenson, Tuuli A1 - Namba, Shinichi A1 - Posner, Daniel C A1 - Kamanu, Frederick K A1 - Koido, Masaru A1 - Le Grand, Quentin A1 - Shi, Mingyang A1 - He, Yunye A1 - Georgakis, Marios K A1 - Caro, Ilana A1 - Krebs, Kristi A1 - Liaw, Yi-Ching A1 - Vaura, Felix C A1 - Lin, Kuang A1 - Winsvold, Bendik Slagsvold A1 - Srinivasasainagendra, Vinodh A1 - Parodi, Livia A1 - Bae, Hee-Joon A1 - Chauhan, Ganesh A1 - Chong, Michael R A1 - Tomppo, Liisa A1 - Akinyemi, Rufus A1 - Roshchupkin, Gennady V A1 - Habib, Naomi A1 - Jee, Yon Ho A1 - Thomassen, Jesper Qvist A1 - Abedi, Vida A1 - Cárcel-Márquez, Jara A1 - Nygaard, Marianne A1 - Leonard, Hampton L A1 - Yang, Chaojie A1 - Yonova-Doing, Ekaterina A1 - Knol, Maria J A1 - Lewis, Adam J A1 - Judy, Renae L A1 - Ago, Tetsuro A1 - Amouyel, Philippe A1 - Armstrong, Nicole D A1 - Bakker, Mark K A1 - Bartz, Traci M A1 - Bennett, David A A1 - Bis, Joshua C A1 - Bordes, Constance A1 - Børte, Sigrid A1 - Cain, Anael A1 - Ridker, Paul M A1 - Cho, Kelly A1 - Chen, Zhengming A1 - Cruchaga, Carlos A1 - Cole, John W A1 - De Jager, Phil L A1 - de Cid, Rafael A1 - Endres, Matthias A1 - Ferreira, Leslie E A1 - Geerlings, Mirjam I A1 - Gasca, Natalie C A1 - Gudnason, Vilmundur A1 - Hata, Jun A1 - He, Jing A1 - Heath, Alicia K A1 - Ho, Yuk-Lam A1 - Havulinna, Aki S A1 - Hopewell, Jemma C A1 - Hyacinth, Hyacinth I A1 - Inouye, Michael A1 - Jacob, Mina A A1 - Jeon, Christina E A1 - Jern, Christina A1 - Kamouchi, Masahiro A1 - Keene, Keith L A1 - Kitazono, Takanari A1 - Kittner, Steven J A1 - Konuma, Takahiro A1 - Kumar, Amit A1 - Lacaze, Paul A1 - Launer, Lenore J A1 - Lee, Keon-Joo A1 - Lepik, Kaido A1 - Li, Jiang A1 - Li, Liming A1 - Manichaikul, Ani A1 - Markus, Hugh S A1 - Marston, Nicholas A A1 - Meitinger, Thomas A1 - Mitchell, Braxton D A1 - Montellano, Felipe A A1 - Morisaki, Takayuki A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Nordestgaard, Børge G A1 - O'Donnell, Martin J A1 - Okada, Yukinori A1 - Onland-Moret, N Charlotte A1 - Ovbiagele, Bruce A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rosand, Jonathan A1 - Sabatine, Marc S A1 - Sacco, Ralph L A1 - Saleheen, Danish A1 - Sandset, Else Charlotte A1 - Salomaa, Veikko A1 - Sargurupremraj, Muralidharan A1 - Sasaki, Makoto A1 - Satizabal, Claudia L A1 - Schmidt, Carsten O A1 - Shimizu, Atsushi A1 - Smith, Nicholas L A1 - Sloane, Kelly L A1 - Sutoh, Yoichi A1 - Sun, Yan V A1 - Tanno, Kozo A1 - Tiedt, Steffen A1 - Tatlisumak, Turgut A1 - Torres-Aguila, Nuria P A1 - Tiwari, Hemant K A1 - Trégouët, David-Alexandre A1 - Trompet, Stella A1 - Tuladhar, Anil Man A1 - Tybjærg-Hansen, Anne A1 - van Vugt, Marion A1 - Vibo, Riina A1 - Verma, Shefali S A1 - Wiggins, Kerri L A1 - Wennberg, Patrik A1 - Woo, Daniel A1 - Wilson, Peter W F A1 - Xu, Huichun A1 - Yang, Qiong A1 - Yoon, Kyungheon A1 - Millwood, Iona Y A1 - Gieger, Christian A1 - Ninomiya, Toshiharu A1 - Grabe, Hans J A1 - Jukema, J Wouter A1 - Rissanen, Ina L A1 - Strbian, Daniel A1 - Kim, Young Jin A1 - Chen, Pei-Hsin A1 - Mayerhofer, Ernst A1 - Howson, Joanna M M A1 - Irvin, Marguerite R A1 - Adams, Hieab A1 - Wassertheil-Smoller, Sylvia A1 - Christensen, Kaare A1 - Ikram, Mohammad A A1 - Rundek, Tatjana A1 - Worrall, Bradford B A1 - Lathrop, G Mark A1 - Riaz, Moeen A1 - Simonsick, Eleanor M A1 - Kõrv, Janika A1 - França, Paulo H C A1 - Zand, Ramin A1 - Prasad, Kameshwar A1 - Frikke-Schmidt, Ruth A1 - de Leeuw, Frank-Erik A1 - Liman, Thomas A1 - Haeusler, Karl Georg A1 - Ruigrok, Ynte M A1 - Heuschmann, Peter Ulrich A1 - Longstreth, W T A1 - Jung, Keum Ji A1 - Bastarache, Lisa A1 - Paré, Guillaume A1 - Damrauer, Scott M A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Anderson, Christopher D A1 - Zwart, John-Anker A1 - Niiranen, Teemu J A1 - Fornage, Myriam A1 - Liaw, Yung-Po A1 - Seshadri, Sudha A1 - Fernandez-Cadenas, Israel A1 - Walters, Robin G A1 - Ruff, Christian T A1 - Owolabi, Mayowa O A1 - Huffman, Jennifer E A1 - Milani, Lili A1 - Kamatani, Yoichiro A1 - Dichgans, Martin A1 - Debette, Stephanie AB -

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

ER - TY - JOUR T1 - Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. 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Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Alaine Broadaway, K A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - 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Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Project, Biobank Japan A1 - BioBank, Penn Medicine A1 - Center, Regeneron Genetics A1 - Consortium, eMERGE A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Geoffrey Hayes, M A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

ER - TY - JOUR T1 - Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. JF - Nature Y1 - 2024 A1 - Suzuki, Ken A1 - Hatzikotoulas, Konstantinos A1 - Southam, Lorraine A1 - Taylor, Henry J A1 - Yin, Xianyong A1 - Lorenz, Kim M A1 - Mandla, Ravi A1 - Huerta-Chagoya, Alicia A1 - Melloni, Giorgio E M A1 - Kanoni, Stavroula A1 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Arruda, Ana Luiza A1 - Sonehara, Kyuto A1 - Namba, Shinichi A1 - Lee, Simon S K A1 - Preuss, Michael H A1 - Petty, Lauren E A1 - Schroeder, Philip A1 - Vanderwerff, Brett A1 - Kals, Mart A1 - Bragg, Fiona A1 - Lin, Kuang A1 - Guo, Xiuqing A1 - Zhang, Weihua A1 - Yao, Jie A1 - Kim, Young Jin A1 - Graff, Mariaelisa A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Moon, Sanghoon A1 - Scott, Robert A A1 - Cook, James P A1 - Lee, Jung-Jin A1 - Pan, Ian A1 - Taliun, Daniel A1 - Parra, Esteban J A1 - Chai, Jin-Fang A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Thorleifsson, Gudmar A1 - Grarup, Niels A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Broadaway, K Alaine A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Thangam, Manonanthini A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Danesh, John A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Gordon-Larsen, Penny A1 - Gross, Myron A1 - Guare, Lindsay A A1 - Hackinger, Sophie A1 - Hakaste, Liisa A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Horikoshi, Momoko A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kamanu, Frederick K A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Moura, Filipe A A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Ahlqvist, Emma A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Marston, Nicholas A A1 - Ruff, Christian T A1 - van Heel, David A A1 - Finer, Sarah A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

ER -