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 - Common genetic determinants of vitamin D insufficiency: a genome-wide association study. JF - Lancet Y1 - 2010 A1 - Wang, Thomas J A1 - Zhang, Feng A1 - Richards, J Brent A1 - Kestenbaum, Bryan A1 - van Meurs, Joyce B A1 - Berry, Diane A1 - Kiel, Douglas P A1 - Streeten, Elizabeth A A1 - Ohlsson, Claes A1 - Koller, Daniel L A1 - Peltonen, Leena A1 - Cooper, Jason D A1 - O'Reilly, Paul F A1 - Houston, Denise K A1 - Glazer, Nicole L A1 - Vandenput, Liesbeth A1 - Peacock, Munro A1 - Shi, Julia A1 - Rivadeneira, Fernando A1 - McCarthy, Mark I A1 - Anneli, Pouta A1 - de Boer, Ian H A1 - Mangino, Massimo A1 - Kato, Bernet A1 - Smyth, Deborah J A1 - Booth, Sarah L A1 - Jacques, Paul F A1 - Burke, Greg L A1 - Goodarzi, Mark A1 - Cheung, Ching-Lung A1 - Wolf, Myles A1 - Rice, Kenneth A1 - Goltzman, David A1 - Hidiroglou, Nick A1 - Ladouceur, Martin A1 - Wareham, Nicholas J A1 - Hocking, Lynne J A1 - Hart, Deborah A1 - Arden, Nigel K A1 - Cooper, Cyrus A1 - Malik, Suneil A1 - Fraser, William D A1 - Hartikainen, Anna-Liisa A1 - Zhai, Guangju A1 - Macdonald, Helen M A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Reid, David M A1 - Hakim, Alan A1 - Dennison, Elaine A1 - Liu, Yongmei A1 - Power, Chris A1 - Stevens, Helen E A1 - Jaana, Laitinen A1 - Vasan, Ramachandran S A1 - Soranzo, Nicole A1 - Bojunga, Jörg A1 - Psaty, Bruce M A1 - Lorentzon, Mattias A1 - Foroud, Tatiana A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Jansson, John-Olov A1 - Cauley, Jane A A1 - Uitterlinden, André G A1 - Gibson, Quince A1 - Jarvelin, Marjo-Riitta A1 - Karasik, David A1 - Siscovick, David S A1 - Econs, Michael J A1 - Kritchevsky, Stephen B A1 - Florez, Jose C A1 - Todd, John A A1 - Dupuis, Josée A1 - Hyppönen, Elina A1 - Spector, Timothy D KW - Canada KW - Chromosomes, Human, Pair 11 KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - Dietary Supplements KW - Europe KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heterozygote KW - Homozygote KW - Humans KW - Immunoassay KW - International Cooperation KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide KW - Seasons KW - United States KW - Vitamin D KW - Vitamin D Deficiency AB -

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

VL - 376 IS - 9736 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20541252?dopt=Abstract ER - TY - JOUR T1 - Differential white blood cell count and type 2 diabetes: systematic review and meta-analysis of cross-sectional and prospective studies. JF - PLoS One Y1 - 2010 A1 - Gkrania-Klotsas, Effrossyni A1 - Ye, Zheng A1 - Cooper, Andrew J A1 - Sharp, Stephen J A1 - Luben, Robert A1 - Biggs, Mary L A1 - Chen, Liang-Kung A1 - Gokulakrishnan, Kuppan A1 - Hanefeld, Markolf A1 - Ingelsson, Erik A1 - Lai, Wen-An A1 - Lin, Shih-Yi A1 - Lind, Lars A1 - Lohsoonthorn, Vitool A1 - Mohan, Viswanathan A1 - Muscari, Antonio A1 - Nilsson, Goran A1 - Ohrvik, John A1 - Chao Qiang, Jiang A1 - Jenny, Nancy Swords A1 - Tamakoshi, Koji A1 - Temelkova-Kurktschiev, Theodora A1 - Wang, Ya-Yu A1 - Yajnik, Chittaranjan Sakerlal A1 - Zoli, Marco A1 - Khaw, Kay-Tee A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Langenberg, Claudia KW - Adult KW - Aged KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Leukocyte Count KW - Male KW - Middle Aged KW - Prospective Studies AB -

OBJECTIVE: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.

RESEARCH DESIGN AND METHODS: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.

RESULTS: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I(2) = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.

CONCLUSIONS: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate.

VL - 5 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20976133?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 - Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies. JF - Diabetes Care Y1 - 2010 A1 - Nettleton, Jennifer A A1 - McKeown, Nicola M A1 - Kanoni, Stavroula A1 - Lemaitre, Rozenn N A1 - Hivert, Marie-France A1 - Ngwa, Julius A1 - van Rooij, Frank J A A1 - Sonestedt, Emily A1 - Wojczynski, Mary K A1 - Ye, Zheng A1 - Tanaka, Tosh A1 - Garcia, Melissa A1 - Anderson, Jennifer S A1 - Follis, Jack L A1 - Djoussé, Luc A1 - Mukamal, Kenneth A1 - Papoutsakis, Constantina A1 - Mozaffarian, Dariush A1 - Zillikens, M Carola A1 - Bandinelli, Stefania A1 - Bennett, Amanda J A1 - Borecki, Ingrid B A1 - Feitosa, Mary F A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Harris, Tamara A1 - Hofman, Albert A1 - Houston, Denise K A1 - Hu, Frank B A1 - Johansson, Ingegerd A1 - Kritchevsky, Stephen B A1 - Langenberg, Claudia A1 - Launer, Lenore A1 - Liu, Yongmei A1 - Loos, Ruth J A1 - Nalls, Michael A1 - Orho-Melander, Marju A1 - Renstrom, Frida A1 - Rice, Kenneth A1 - Riserus, Ulf A1 - Rolandsson, Olov A1 - Rotter, Jerome I A1 - Saylor, Georgia A1 - Sijbrands, Eric J G A1 - Sjogren, Per A1 - Smith, Albert A1 - Steingrímsdóttir, Laufey A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Prokopenko, Inga A1 - Pankow, James S A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Witteman, Jacqueline C M A1 - Dupuis, Josée A1 - Dedoussis, George V A1 - Ordovas, Jose M A1 - Ingelsson, Erik A1 - Cupples, L Adrienne A1 - Siscovick, David S A1 - Franks, Paul W A1 - Meigs, James B KW - Adult KW - Aged KW - Blood Glucose KW - Edible Grain KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

OBJECTIVE: Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin.

RESEARCH DESIGN AND METHODS: Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant.

RESULTS: Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele.

CONCLUSIONS: Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20693352?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 - New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. JF - Nat Genet Y1 - 2010 A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Prokopenko, Inga A1 - Saxena, Richa A1 - Soranzo, Nicole A1 - Jackson, Anne U A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Gloyn, Anna L A1 - Lindgren, Cecilia M A1 - Mägi, Reedik A1 - Morris, Andrew P A1 - Randall, Joshua A1 - Johnson, Toby A1 - Elliott, Paul A1 - Rybin, Denis A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Henneman, Peter A1 - Grallert, Harald A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Franklin, Christopher S A1 - Navarro, Pau A1 - Song, Kijoung A1 - Goel, Anuj A1 - Perry, John R B A1 - Egan, Josephine M A1 - Lajunen, Taina A1 - Grarup, Niels A1 - Sparsø, Thomas A1 - Doney, Alex A1 - Voight, Benjamin F A1 - Stringham, Heather M A1 - Li, Man A1 - Kanoni, Stavroula A1 - Shrader, Peter A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Qi, Lu A1 - Timpson, Nicholas J A1 - Gieger, Christian A1 - Zabena, Carina A1 - Rocheleau, Ghislain A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Payne, Felicity A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ardlie, Kristin A1 - Ariyurek, Yavuz A1 - Balkau, Beverley A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bonnefond, Amélie A1 - Bonnycastle, Lori L A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Charpentier, Guillaume A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Dina, Christian A1 - Erdos, Michael R A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Fox, Caroline S A1 - Frants, Rune A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Groves, Christopher J A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Gyllensten, Ulf A1 - Hadjadj, Samy A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hassanali, Neelam A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Herder, Christian A1 - Hicks, Andrew A A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Hui, Jennie A1 - Hung, Joe A1 - Isomaa, Bo A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Jula, Antti 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 - Lyssenko, Valeriya A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Manning, Alisa K A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McCulloch, Laura J A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Morken, Mario A A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Narisu, Narisu A1 - Neville, Matthew J A1 - Oostra, Ben A A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Palmer, Colin N A A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Perola, Markus 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 - Psaty, Bruce M A1 - Rathmann, Wolfgang A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Roden, Michael A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Scott, Laura J A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurethsson, 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 - Tanaka, Toshiko A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tönjes, Anke A1 - Tuomi, Tiinamaija A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - van Hoek, Mandy A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Walters, G Bragi A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Weedon, Michael N A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zeggini, Eleftheria A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Loos, Ruth J F A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Hattersley, Andrew T A1 - Silander, Kaisa A1 - Salomaa, Veikko A1 - Smith, George Davey A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Serrano-Ríos, Manuel A1 - Morris, Andrew D 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 - Pankow, James S A1 - Sampson, Michael J A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Pramstaller, Peter Paul A1 - Wichmann, H Erich A1 - Illig, Thomas A1 - Rudan, Igor A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Campbell, Harry A1 - Wilson, James F A1 - Bergman, Richard N A1 - Buchanan, Thomas A A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - Valle, Timo T A1 - Altshuler, David A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Deloukas, Panos A1 - Spector, Timothy D A1 - Frayling, Timothy M A1 - Ferrucci, Luigi A1 - Kong, Augustine A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Aulchenko, Yurii S A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Waterworth, Dawn M A1 - Vollenweider, Peter A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Abecasis, Goncalo R A1 - Wareham, Nicholas J A1 - Sladek, Robert A1 - Froguel, Philippe A1 - Watanabe, Richard M A1 - Meigs, James B A1 - Groop, Leif A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Florez, Jose C A1 - Barroso, Inês KW - Adolescent KW - Adult KW - Alleles KW - Blood Glucose KW - Child KW - Databases, Genetic KW - Diabetes Mellitus, Type 2 KW - DNA Copy Number Variations KW - Fasting KW - Gene Expression Regulation KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Homeostasis KW - Humans KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Quantitative Trait, Heritable KW - Reproducibility of Results AB -

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20081858?dopt=Abstract ER - TY - JOUR T1 - CUBN is a gene locus for albuminuria. JF - J Am Soc Nephrol Y1 - 2011 A1 - Böger, Carsten A A1 - Chen, Ming-Huei A1 - Tin, Adrienne A1 - Olden, Matthias A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Fuchsberger, Christian A1 - O'Seaghdha, Conall M A1 - Pattaro, Cristian A1 - Teumer, Alexander A1 - Liu, Ching-Ti A1 - Glazer, Nicole L A1 - Li, Man A1 - O'Connell, Jeffrey R A1 - Tanaka, Toshiko A1 - Peralta, Carmen A A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Zhao, Jing Hua A1 - Hwang, Shih-Jen A1 - Akylbekova, Ermeg A1 - Kramer, Holly A1 - van der Harst, Pim A1 - Smith, Albert V A1 - Lohman, Kurt A1 - de Andrade, Mariza A1 - Hayward, Caroline A1 - Kollerits, Barbara A1 - Tönjes, Anke A1 - Aspelund, Thor A1 - Ingelsson, Erik A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Shuldiner, Alan R A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Franceschini, Nora A1 - Boerwinkle, Eric A1 - Egan, Josephine A1 - Hernandez, Dena A1 - Reilly, Muredach A1 - Townsend, Raymond R A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Kestenbaum, Bryan A1 - Haritunians, Talin A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Mooser, Vincent A1 - Waterworth, Dawn A1 - Johnson, Andrew D A1 - Florez, Jose C A1 - Meigs, James B A1 - Lu, Xiaoning A1 - Turner, Stephen T A1 - Atkinson, Elizabeth J A1 - Leak, Tennille S A1 - Aasarød, Knut A1 - Skorpen, Frank A1 - Syvänen, Ann-Christine A1 - Illig, Thomas A1 - Baumert, Jens A1 - Koenig, Wolfgang A1 - Krämer, Bernhard K A1 - Devuyst, Olivier A1 - Mychaleckyj, Josyf C A1 - Minelli, Cosetta A1 - Bakker, Stephan J L A1 - Kedenko, Lyudmyla A1 - Paulweber, Bernhard A1 - Coassin, Stefan A1 - Endlich, Karlhans A1 - Kroemer, Heyo K A1 - Biffar, Reiner A1 - Stracke, Sylvia A1 - Völzke, Henry A1 - Stumvoll, Michael A1 - Mägi, Reedik A1 - Campbell, Harry A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Polasek, Ozren A1 - Curhan, Gary A1 - Kronenberg, Florian A1 - Prokopenko, Inga A1 - Rudan, Igor A1 - Arnlöv, Johan A1 - Hallan, Stein A1 - Navis, Gerjan A1 - Parsa, Afshin A1 - Ferrucci, Luigi A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Bull, Shelley B A1 - Paterson, Nicholas J A1 - Wichmann, H-Erich A1 - Wareham, Nicholas J A1 - Loos, Ruth J F A1 - Rotter, Jerome I A1 - Pramstaller, Peter P A1 - Cupples, L Adrienne A1 - Beckmann, Jacques S A1 - Yang, Qiong A1 - Heid, Iris M A1 - Rettig, Rainer A1 - Dreisbach, Albert W A1 - Bochud, Murielle A1 - Fox, Caroline S A1 - Kao, W H L KW - African Continental Ancestry Group KW - Albuminuria KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Humans KW - Mutation, Missense KW - Receptors, Cell Surface AB -

Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.

VL - 22 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21355061?dopt=Abstract ER - TY - JOUR T1 - Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. JF - Nature Y1 - 2011 A1 - Ehret, Georg B A1 - Munroe, Patricia B A1 - Rice, Kenneth M A1 - Bochud, Murielle A1 - Johnson, Andrew D A1 - Chasman, Daniel I A1 - Smith, Albert V A1 - Tobin, Martin D A1 - Verwoert, Germaine C A1 - Hwang, Shih-Jen A1 - Pihur, Vasyl A1 - Vollenweider, Peter A1 - O'Reilly, Paul F A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Launer, Lenore A1 - Zhao, Jing Hua A1 - Aulchenko, Yurii A1 - Heath, Simon A1 - Sõber, Siim A1 - Parsa, Afshin A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Dehghan, Abbas A1 - Zhang, Feng A1 - Lucas, Gavin A1 - Hicks, Andrew A A1 - Jackson, Anne U A1 - Peden, John F A1 - Tanaka, Toshiko A1 - Wild, Sarah H A1 - Rudan, Igor A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Parker, Alex N A1 - Fava, Cristiano A1 - Chambers, John C A1 - Fox, Ervin R A1 - Kumari, Meena A1 - Go, Min Jin A1 - van der Harst, Pim A1 - Kao, Wen Hong Linda A1 - Sjögren, Marketa A1 - Vinay, D G A1 - Alexander, Myriam A1 - Tabara, Yasuharu A1 - Shaw-Hawkins, Sue A1 - Whincup, Peter H A1 - Liu, Yongmei A1 - Shi, Gang A1 - Kuusisto, Johanna A1 - Tayo, Bamidele A1 - Seielstad, Mark A1 - Sim, Xueling A1 - Nguyen, Khanh-Dung Hoang A1 - Lehtimäki, Terho A1 - Matullo, Giuseppe A1 - Wu, Ying A1 - Gaunt, Tom R A1 - Onland-Moret, N Charlotte A1 - Cooper, Matthew N A1 - Platou, Carl G P A1 - Org, Elin A1 - Hardy, Rebecca A1 - Dahgam, Santosh A1 - Palmen, Jutta A1 - Vitart, Veronique A1 - Braund, Peter S A1 - Kuznetsova, Tatiana A1 - Uiterwaal, Cuno S P M A1 - Adeyemo, Adebowale A1 - Palmas, Walter A1 - Campbell, Harry A1 - Ludwig, Barbara A1 - Tomaszewski, Maciej A1 - Tzoulaki, Ioanna A1 - Palmer, Nicholette D A1 - Aspelund, Thor A1 - Garcia, Melissa A1 - Chang, Yen-Pei C A1 - O'Connell, Jeffrey R A1 - Steinle, Nanette I A1 - Grobbee, Diederick E A1 - Arking, Dan E A1 - Kardia, Sharon L A1 - Morrison, Alanna C A1 - Hernandez, Dena A1 - Najjar, Samer A1 - McArdle, Wendy L A1 - Hadley, David A1 - Brown, Morris J A1 - 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Vineis, Paolo A1 - Raitakari, Olli A1 - Ganesh, Santhi K A1 - Wong, Tien Y A1 - Tai, E Shyong A1 - Cooper, Richard S A1 - Laakso, Markku A1 - Rao, Dabeeru C A1 - Harris, Tamara B A1 - Morris, Richard W A1 - Dominiczak, Anna F A1 - Kivimaki, Mika A1 - Marmot, Michael G A1 - Miki, Tetsuro A1 - Saleheen, Danish A1 - Chandak, Giriraj R A1 - Coresh, Josef A1 - Navis, Gerjan A1 - Salomaa, Veikko A1 - Han, Bok-Ghee A1 - Zhu, Xiaofeng A1 - Kooner, Jaspal S A1 - Melander, Olle A1 - Ridker, Paul M A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wright, Alan F A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Farrall, Martin A1 - Tuomilehto, Jaakko A1 - Pramstaller, Peter P A1 - Elosua, Roberto A1 - Soranzo, Nicole A1 - Sijbrands, Eric J G A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Shuldiner, Alan R A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Gudnason, Vilmundur A1 - Rotter, Jerome I A1 - Rettig, Rainer A1 - Uda, Manuela A1 - Strachan, David P A1 - Witteman, Jacqueline C M A1 - Hartikainen, Anna-Liisa A1 - Beckmann, Jacques S A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S A1 - Boehnke, Michael A1 - Larson, Martin G A1 - Jarvelin, Marjo-Riitta A1 - Psaty, Bruce M A1 - Abecasis, Goncalo R A1 - Chakravarti, Aravinda A1 - Elliott, Paul A1 - van Duijn, Cornelia M A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Caulfield, Mark J A1 - Johnson, Toby KW - Africa KW - Asia KW - Blood Pressure KW - Cardiovascular Diseases KW - Coronary Artery Disease KW - Europe KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Kidney Diseases KW - Polymorphism, Single Nucleotide KW - Stroke AB -

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

VL - 478 IS - 7367 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909115?dopt=Abstract ER - TY - JOUR T1 - Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile. JF - Nat Genet Y1 - 2011 A1 - Kilpeläinen, Tuomas O A1 - Zillikens, M Carola A1 - Stančáková, Alena A1 - Finucane, Francis M A1 - Ried, Janina S A1 - Langenberg, Claudia A1 - Zhang, Weihua A1 - Beckmann, Jacques S A1 - Luan, Jian'an A1 - Vandenput, Liesbeth A1 - Styrkarsdottir, Unnur A1 - Zhou, Yanhua A1 - Smith, Albert Vernon A1 - Zhao, Jing-Hua A1 - Amin, Najaf A1 - Vedantam, Sailaja A1 - Shin, So-Youn A1 - Haritunians, Talin A1 - Fu, Mao A1 - Feitosa, Mary F A1 - Kumari, Meena A1 - Halldorsson, Bjarni V A1 - Tikkanen, Emmi A1 - Mangino, Massimo A1 - Hayward, Caroline A1 - Song, Ci A1 - Arnold, Alice M A1 - Aulchenko, Yurii S A1 - Oostra, Ben A A1 - Campbell, Harry A1 - Cupples, L Adrienne A1 - Davis, Kathryn E A1 - Döring, Angela A1 - Eiriksdottir, Gudny A1 - Estrada, Karol A1 - Fernández-Real, José Manuel A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Glazer, Nicole L A1 - Guiducci, Candace A1 - Hofman, Albert A1 - Humphries, Steve E A1 - Isomaa, Bo A1 - Jacobs, Leonie C A1 - Jula, Antti A1 - Karasik, David A1 - Karlsson, Magnus K A1 - Khaw, Kay-Tee A1 - Kim, Lauren J A1 - Kivimaki, Mika A1 - Klopp, Norman A1 - Kuhnel, Brigitte A1 - Kuusisto, Johanna A1 - Liu, Yongmei A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - McKnight, Barbara A1 - Mellström, Dan A1 - Mitchell, Braxton D A1 - Mooser, Vincent A1 - Moreno, José Maria A1 - Männistö, Satu A1 - O'Connell, Jeffery R A1 - Pascoe, Laura A1 - Peltonen, Leena A1 - Peral, Belén A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Salomaa, Veikko A1 - Savage, David B A1 - Semple, Robert K A1 - Skaric-Juric, Tatjana A1 - Sigurdsson, Gunnar A1 - Song, Kijoung S A1 - Spector, Timothy D A1 - Syvänen, Ann-Christine A1 - Talmud, Philippa J A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Vidal-Puig, Antonio A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Clegg, Deborah J A1 - Schadt, Eric A1 - Wilson, James F A1 - Rudan, Igor A1 - Ripatti, Samuli A1 - Borecki, Ingrid B A1 - Shuldiner, Alan R A1 - Ingelsson, Erik A1 - Jansson, John-Olov A1 - Kaplan, Robert C A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Groop, Leif A1 - Kiel, Douglas P A1 - Rivadeneira, Fernando A1 - Walker, Mark A1 - Barroso, Inês A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Chambers, John C A1 - Kooner, Jaspal S A1 - Soranzo, Nicole A1 - Hirschhorn, Joel N A1 - Stefansson, Kari A1 - Wichmann, H-Erich A1 - Ohlsson, Claes A1 - O'Rahilly, Stephen A1 - Wareham, Nicholas J A1 - Speliotes, Elizabeth K A1 - Fox, Caroline S A1 - Laakso, Markku A1 - Loos, Ruth J F KW - Adiponectin KW - Adiposity KW - Alleles KW - Body Fat Distribution KW - Body Mass Index KW - Body Weight KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Insulin Receptor Substrate Proteins KW - Intracellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Meta-Analysis as Topic KW - Metabolome KW - Obesity KW - Polymorphism, Single Nucleotide KW - Subcutaneous Fat AB -

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ∼2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.

VL - 43 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21706003?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. JF - Nat Genet Y1 - 2011 A1 - Soler Artigas, Maria A1 - Loth, Daan W A1 - Wain, Louise V A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Tang, Wenbo A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Smith, Albert Vernon A1 - Huffman, Jennifer E A1 - Albrecht, Eva A1 - Jackson, Catherine M A1 - Evans, David M A1 - Cadby, Gemma A1 - Fornage, Myriam A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Johnson, Toby A1 - Aldrich, Melinda C A1 - Aspelund, Thor A1 - Barroso, Inês A1 - Campbell, Harry A1 - Cassano, Patricia A A1 - Couper, David J A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Gislason, Gauti Kjartan A1 - Grkovic, Ivica A1 - Hammond, Christopher J A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Ramasamy, Adaikalavan A1 - Heckbert, Susan R A1 - Heliövaara, Markku A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - James, Alan L A1 - Jankovic, Stipan A1 - Joubert, Bonnie R A1 - Karrasch, Stefan A1 - Klopp, Norman A1 - Koch, Beate A1 - Kritchevsky, Stephen B A1 - Launer, Lenore J A1 - Liu, Yongmei A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Lumley, Thomas A1 - Al Balushi, Khalid A A1 - Ang, Wei Q A1 - Barr, R Graham A1 - Beilby, John A1 - Blakey, John D A1 - Boban, Mladen A1 - Boraska, Vesna A1 - Brisman, Jonas A1 - Britton, John R A1 - Brusselle, Guy G A1 - Cooper, Cyrus A1 - Curjuric, Ivan A1 - Dahgam, Santosh A1 - Deary, Ian J A1 - Ebrahim, Shah A1 - Eijgelsheim, Mark A1 - Francks, Clyde A1 - Gaysina, Darya A1 - Granell, Raquel A1 - Gu, Xiangjun A1 - Hankinson, John L A1 - Hardy, Rebecca A1 - Harris, Sarah E A1 - Henderson, John A1 - Henry, Amanda A1 - Hingorani, Aroon D A1 - Hofman, Albert A1 - Holt, Patrick G A1 - Hui, Jennie A1 - Hunter, Michael L A1 - Imboden, Medea A1 - Jameson, Karen A A1 - Kerr, Shona M A1 - Kolcic, Ivana A1 - Kronenberg, Florian A1 - Liu, Jason Z A1 - Marchini, Jonathan A1 - McKeever, Tricia A1 - Morris, Andrew D A1 - Olin, Anna-Carin A1 - Porteous, David J A1 - Postma, Dirkje S A1 - Rich, Stephen S A1 - Ring, Susan M A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Sayer, Avan Aihie A1 - Sayers, Ian A1 - Sly, Peter D A1 - Smith, George Davey A1 - Sood, Akshay A1 - Starr, John M A1 - Uitterlinden, André G A1 - Vonk, Judith M A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Wong, Andrew A1 - Mangino, Massimo A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - North, Kari E A1 - Omenaas, Ernst A1 - Palmer, Lyle J A1 - Pietiläinen, Kirsi H A1 - Pin, Isabelle A1 - Pola Sbreve Ek, Ozren A1 - Pouta, Anneli A1 - Psaty, Bruce M A1 - Hartikainen, Anna-Liisa A1 - Rantanen, Taina A1 - Ripatti, Samuli A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Rudnicka, Alicja R A1 - Schulz, Holger A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Surakka, Ida A1 - Vitart, Veronique A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Warrington, Nicole M A1 - Wichmann, H-Erich A1 - Wild, Sarah H A1 - Wilk, Jemma B A1 - Wjst, Matthias A1 - Wright, Alan F A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Pennell, Craig E A1 - Nyberg, Fredrik A1 - Kuh, Diana A1 - Holloway, John W A1 - Boezen, H Marike A1 - Lawlor, Debbie A A1 - Morris, Richard W A1 - Probst-Hensch, Nicole A1 - Kaprio, Jaakko A1 - Wilson, James F A1 - Hayward, Caroline A1 - Kähönen, Mika A1 - Heinrich, Joachim A1 - Musk, Arthur W A1 - Jarvis, Deborah L A1 - Gläser, Sven A1 - Jarvelin, Marjo-Riitta A1 - Ch Stricker, Bruno H A1 - Elliott, Paul A1 - O'Connor, George T A1 - Strachan, David P A1 - London, Stephanie J A1 - Hall, Ian P A1 - Gudnason, Vilmundur A1 - Tobin, Martin D KW - Child KW - European Continental Ancestry Group KW - Genome-Wide Association Study KW - Humans KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests AB -

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

VL - 43 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. JF - Nat Genet Y1 - 2011 A1 - Wain, Louise V A1 - Verwoert, Germaine C A1 - O'Reilly, Paul F A1 - Shi, Gang A1 - Johnson, Toby A1 - Johnson, Andrew D A1 - Bochud, Murielle A1 - Rice, Kenneth M A1 - Henneman, Peter A1 - Smith, Albert V A1 - Ehret, Georg B A1 - Amin, Najaf A1 - Larson, Martin G A1 - Mooser, Vincent A1 - Hadley, David A1 - Dörr, Marcus A1 - Bis, Joshua C A1 - Aspelund, Thor A1 - Esko, Tõnu A1 - Janssens, A Cecile J W A1 - Zhao, Jing Hua A1 - Heath, Simon A1 - Laan, Maris A1 - Fu, Jingyuan A1 - Pistis, Giorgio A1 - Luan, Jian'an A1 - Arora, Pankaj A1 - Lucas, Gavin A1 - Pirastu, Nicola A1 - Pichler, Irene A1 - Jackson, Anne U A1 - Webster, Rebecca J A1 - Zhang, Feng A1 - Peden, John F A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Campbell, Harry A1 - Igl, Wilmar A1 - Milaneschi, Yuri A1 - Hottenga, Jouke-Jan A1 - Vitart, Veronique A1 - Chasman, Daniel I A1 - Trompet, Stella A1 - Bragg-Gresham, Jennifer L A1 - Alizadeh, Behrooz Z A1 - Chambers, John C A1 - Guo, Xiuqing A1 - Lehtimäki, Terho A1 - Kuhnel, Brigitte A1 - Lopez, Lorna M A1 - Polasek, Ozren A1 - Boban, Mladen A1 - Nelson, Christopher P A1 - Morrison, Alanna C A1 - Pihur, Vasyl A1 - Ganesh, Santhi K A1 - Hofman, Albert A1 - Kundu, Suman A1 - Mattace-Raso, Francesco U S A1 - Rivadeneira, Fernando A1 - Sijbrands, Eric J G A1 - Uitterlinden, André G A1 - Hwang, Shih-Jen A1 - Vasan, Ramachandran S A1 - Wang, Thomas J A1 - Bergmann, Sven A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Zitting, Paavo A1 - McArdle, Wendy L A1 - Kroemer, Heyo K A1 - Völker, Uwe A1 - Völzke, Henry A1 - Glazer, Nicole L A1 - Taylor, Kent D A1 - Harris, Tamara B A1 - Alavere, Helene A1 - Haller, Toomas A1 - Keis, Aime A1 - Tammesoo, Mari-Liis A1 - Aulchenko, Yurii A1 - Barroso, Inês A1 - Khaw, Kay-Tee A1 - Galan, Pilar A1 - Hercberg, Serge A1 - Lathrop, Mark A1 - Eyheramendy, Susana A1 - Org, Elin A1 - Sõber, Siim A1 - Lu, Xiaowen A1 - Nolte, Ilja M A1 - Penninx, Brenda W A1 - Corre, Tanguy A1 - Masciullo, Corrado A1 - Sala, Cinzia A1 - Groop, Leif A1 - Voight, Benjamin F A1 - Melander, Olle A1 - O'Donnell, Christopher J A1 - Salomaa, Veikko A1 - d'Adamo, Adamo Pio A1 - Fabretto, Antonella A1 - Faletra, Flavio A1 - Ulivi, Sheila A1 - Del Greco, Fabiola M A1 - Facheris, Maurizio A1 - Collins, Francis S A1 - Bergman, Richard N A1 - Beilby, John P A1 - Hung, Joseph A1 - Musk, A William A1 - Mangino, Massimo A1 - Shin, So-Youn A1 - Soranzo, Nicole A1 - Watkins, Hugh A1 - Goel, Anuj A1 - Hamsten, Anders A1 - Gider, Pierre A1 - Loitfelder, Marisa A1 - Zeginigg, Marion A1 - Hernandez, Dena A1 - Najjar, Samer S A1 - Navarro, Pau A1 - Wild, Sarah H A1 - Corsi, Anna Maria A1 - Singleton, Andrew A1 - de Geus, Eco J C A1 - Willemsen, Gonneke A1 - Parker, Alex N A1 - Rose, Lynda M A1 - Buckley, Brendan A1 - Stott, David A1 - Orrù, Marco A1 - Uda, Manuela A1 - van der Klauw, Melanie M A1 - Zhang, Weihua A1 - Li, Xinzhong A1 - Scott, James A1 - Chen, Yii-Der Ida A1 - Burke, Gregory L A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Döring, Angela A1 - Meitinger, Thomas A1 - Davies, Gail A1 - Starr, John M A1 - Emilsson, Valur A1 - Plump, Andrew A1 - Lindeman, Jan H A1 - Hoen, Peter A C 't A1 - König, Inke R A1 - Felix, Janine F A1 - Clarke, Robert A1 - Hopewell, Jemma C A1 - Ongen, Halit A1 - Breteler, Monique A1 - Debette, Stephanie A1 - DeStefano, Anita L A1 - Fornage, Myriam A1 - Mitchell, Gary F A1 - Smith, Nicholas L A1 - Holm, Hilma A1 - Stefansson, Kari A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Samani, Nilesh J A1 - Preuss, Michael A1 - Rudan, Igor A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Wichmann, H-Erich A1 - Raitakari, Olli T A1 - Palmas, Walter A1 - Kooner, Jaspal S A1 - Stolk, Ronald P A1 - Jukema, J Wouter A1 - Wright, Alan F A1 - Boomsma, Dorret I A1 - Bandinelli, Stefania A1 - Gyllensten, Ulf B A1 - Wilson, James F A1 - Ferrucci, Luigi A1 - Schmidt, Reinhold A1 - Farrall, Martin A1 - Spector, Tim D A1 - Palmer, Lyle J A1 - Tuomilehto, Jaakko A1 - Pfeufer, Arne A1 - Gasparini, Paolo A1 - Siscovick, David A1 - Altshuler, David A1 - Loos, Ruth J F A1 - Toniolo, Daniela A1 - Snieder, Harold A1 - Gieger, Christian A1 - Meneton, Pierre A1 - Wareham, Nicholas J A1 - Oostra, Ben A A1 - Metspalu, Andres A1 - Launer, Lenore A1 - Rettig, Rainer A1 - Strachan, David P A1 - Beckmann, Jacques S A1 - Witteman, Jacqueline C M A1 - Erdmann, Jeanette A1 - van Dijk, Ko Willems A1 - Boerwinkle, Eric A1 - Boehnke, Michael A1 - Ridker, Paul M A1 - Jarvelin, Marjo-Riitta A1 - Chakravarti, Aravinda A1 - Abecasis, Goncalo R A1 - Gudnason, Vilmundur A1 - Newton-Cheh, Christopher A1 - Levy, Daniel A1 - Munroe, Patricia B A1 - Psaty, Bruce M A1 - Caulfield, Mark J A1 - Rao, Dabeeru C A1 - Tobin, Martin D A1 - Elliott, Paul A1 - van Duijn, Cornelia M KW - Arteries KW - Blood Pressure KW - Case-Control Studies KW - Follow-Up Studies KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide AB -

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

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909110?dopt=Abstract ER - TY - JOUR T1 - New gene functions in megakaryopoiesis and platelet formation. JF - Nature Y1 - 2011 A1 - Gieger, Christian A1 - Radhakrishnan, Aparna A1 - Cvejic, Ana A1 - Tang, Weihong A1 - Porcu, Eleonora A1 - Pistis, Giorgio A1 - Serbanovic-Canic, Jovana A1 - Elling, Ulrich A1 - Goodall, Alison H A1 - Labrune, Yann A1 - Lopez, Lorna M A1 - Mägi, Reedik A1 - Meacham, Stuart A1 - Okada, Yukinori A1 - Pirastu, Nicola A1 - Sorice, Rossella A1 - Teumer, Alexander A1 - Voss, Katrin A1 - Zhang, Weihua A1 - Ramirez-Solis, Ramiro A1 - Bis, Joshua C A1 - Ellinghaus, David A1 - Gögele, Martin A1 - Hottenga, Jouke-Jan A1 - Langenberg, Claudia A1 - Kovacs, Peter A1 - O'Reilly, Paul F A1 - Shin, So-Youn A1 - Esko, Tõnu A1 - Hartiala, Jaana A1 - Kanoni, Stavroula A1 - Murgia, Federico A1 - Parsa, Afshin A1 - Stephens, Jonathan A1 - van der Harst, Pim A1 - Ellen van der Schoot, C A1 - Allayee, Hooman A1 - Attwood, Antony A1 - Balkau, Beverley A1 - Bastardot, François A1 - Basu, Saonli A1 - Baumeister, Sebastian E A1 - Biino, Ginevra A1 - Bomba, Lorenzo A1 - Bonnefond, Amélie A1 - Cambien, Francois A1 - Chambers, John C A1 - Cucca, Francesco A1 - D'Adamo, Pio A1 - Davies, Gail A1 - de Boer, Rudolf A A1 - de Geus, Eco J C A1 - Döring, Angela A1 - Elliott, Paul A1 - Erdmann, Jeanette A1 - Evans, David M A1 - Falchi, Mario A1 - Feng, Wei A1 - Folsom, Aaron R A1 - Frazer, Ian H A1 - Gibson, Quince D A1 - Glazer, Nicole L A1 - Hammond, Chris A1 - Hartikainen, Anna-Liisa A1 - Heckbert, Susan R A1 - Hengstenberg, Christian A1 - Hersch, Micha A1 - Illig, Thomas A1 - Loos, Ruth J F A1 - Jolley, Jennifer A1 - Khaw, Kay Tee A1 - Kuhnel, Brigitte A1 - Kyrtsonis, Marie-Christine A1 - Lagou, Vasiliki A1 - Lloyd-Jones, Heather A1 - Lumley, Thomas A1 - Mangino, Massimo A1 - Maschio, Andrea A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Memari, Yasin A1 - Mitchell, Braxton D A1 - Montgomery, Grant W A1 - Nakamura, Yusuke A1 - Nauck, Matthias A1 - Navis, Gerjan A1 - Nöthlings, Ute A1 - Nolte, Ilja M A1 - Porteous, David J A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Pullat, Janne A1 - Ring, Susan M A1 - Rotter, Jerome I A1 - Ruggiero, Daniela A1 - Ruokonen, Aimo A1 - Sala, Cinzia A1 - Samani, Nilesh J A1 - Sambrook, Jennifer A1 - Schlessinger, David A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Scott, James A1 - Smith, Nicholas L A1 - Snieder, Harold A1 - Starr, John M A1 - Stumvoll, Michael A1 - Takahashi, Atsushi A1 - Tang, W H Wilson A1 - Taylor, Kent A1 - Tenesa, Albert A1 - Lay Thein, Swee A1 - Tönjes, Anke A1 - Uda, Manuela A1 - Ulivi, Sheila A1 - van Veldhuisen, Dirk J A1 - Visscher, Peter M A1 - Völker, Uwe A1 - Wichmann, H-Erich A1 - Wiggins, Kerri L A1 - Willemsen, Gonneke A1 - Yang, Tsun-Po A1 - Hua Zhao, Jing A1 - Zitting, Paavo A1 - Bradley, John R A1 - Dedoussis, George V A1 - Gasparini, Paolo A1 - Hazen, Stanley L A1 - Metspalu, Andres A1 - Pirastu, Mario A1 - Shuldiner, Alan R A1 - Joost van Pelt, L A1 - Zwaginga, Jaap-Jan A1 - Boomsma, Dorret I A1 - Deary, Ian J A1 - Franke, Andre A1 - Froguel, Philippe A1 - Ganesh, Santhi K A1 - Jarvelin, Marjo-Riitta A1 - Martin, Nicholas G A1 - Meisinger, Christa A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Wareham, Nicholas J A1 - Akkerman, Jan-Willem N A1 - Ciullo, Marina A1 - Deloukas, Panos A1 - Greinacher, Andreas A1 - Jupe, Steve A1 - Kamatani, Naoyuki A1 - Khadake, Jyoti A1 - Kooner, Jaspal S A1 - Penninger, Josef A1 - Prokopenko, Inga A1 - Stemple, Derek A1 - Toniolo, Daniela A1 - Wernisch, Lorenz A1 - Sanna, Serena A1 - Hicks, Andrew A A1 - Rendon, Augusto A1 - Ferreira, Manuel A A1 - Ouwehand, Willem H A1 - Soranzo, Nicole KW - Animals KW - Blood Platelets KW - Cell Size KW - Drosophila melanogaster KW - Drosophila Proteins KW - Europe KW - Gene Expression Profiling KW - Gene Silencing KW - Genome, Human KW - Genome-Wide Association Study KW - Hematopoiesis KW - Humans KW - Megakaryocytes KW - Platelet Count KW - Protein Interaction Maps KW - Transcription, Genetic KW - Zebrafish KW - Zebrafish Proteins AB -

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

VL - 480 IS - 7376 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22139419?dopt=Abstract ER - TY - JOUR T1 - FTO genotype is associated with phenotypic variability of body mass index. JF - Nature Y1 - 2012 A1 - Yang, Jian A1 - Loos, Ruth J F A1 - Powell, Joseph E A1 - Medland, Sarah E A1 - Speliotes, Elizabeth K A1 - Chasman, Daniel I A1 - Rose, Lynda M A1 - Thorleifsson, Gudmar A1 - Steinthorsdottir, Valgerdur A1 - Mägi, Reedik A1 - Waite, Lindsay A1 - Smith, Albert Vernon A1 - Yerges-Armstrong, Laura M A1 - Monda, Keri L A1 - Hadley, David A1 - Mahajan, Anubha A1 - Li, Guo A1 - Kapur, Karen A1 - Vitart, Veronique A1 - Huffman, Jennifer E A1 - Wang, Sophie R A1 - Palmer, Cameron A1 - Esko, Tõnu A1 - Fischer, Krista A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Isaacs, Aaron A1 - Feitosa, Mary F A1 - Luan, Jian'an A1 - Heard-Costa, Nancy L A1 - White, Charles A1 - Jackson, Anne U A1 - Preuss, Michael A1 - Ziegler, Andreas A1 - Eriksson, Joel A1 - Kutalik, Zoltán A1 - Frau, Francesca A1 - Nolte, Ilja M A1 - van Vliet-Ostaptchouk, Jana V A1 - Hottenga, Jouke-Jan A1 - Jacobs, Kevin B A1 - Verweij, Niek A1 - Goel, Anuj A1 - Medina-Gómez, Carolina A1 - Estrada, Karol A1 - Bragg-Gresham, Jennifer Lynn A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Tyrer, Jonathan A1 - Teumer, Alexander A1 - Prokopenko, Inga A1 - Mangino, Massimo A1 - Lindgren, Cecilia M A1 - Assimes, Themistocles L A1 - Shuldiner, Alan R A1 - Hui, Jennie A1 - Beilby, John P A1 - McArdle, Wendy L A1 - Hall, Per A1 - Haritunians, Talin A1 - Zgaga, Lina A1 - Kolcic, Ivana A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Oostra, Ben A A1 - Junttila, M Juhani A1 - Grönberg, Henrik A1 - Schreiber, Stefan A1 - Peters, Annette A1 - Hicks, Andrew A A1 - Stephens, Jonathan A1 - Foad, Nicola S A1 - Laitinen, Jaana A1 - Pouta, Anneli A1 - Kaakinen, Marika A1 - Willemsen, Gonneke A1 - Vink, Jacqueline M A1 - Wild, Sarah H A1 - Navis, Gerjan A1 - Asselbergs, Folkert W A1 - Homuth, Georg A1 - John, Ulrich A1 - Iribarren, Carlos A1 - Harris, Tamara A1 - Launer, Lenore A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Boerwinkle, Eric A1 - Cadby, Gemma A1 - Palmer, Lyle J A1 - James, Alan L A1 - Musk, Arthur W A1 - Ingelsson, Erik A1 - Psaty, Bruce M A1 - Beckmann, Jacques S A1 - Waeber, Gérard A1 - Vollenweider, Peter A1 - Hayward, Caroline A1 - Wright, Alan F A1 - Rudan, Igor A1 - Groop, Leif C A1 - Metspalu, Andres A1 - Khaw, Kay Tee A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Province, Michael A A1 - Wareham, Nicholas J A1 - Tardif, Jean-Claude A1 - Huikuri, Heikki V A1 - Cupples, L Adrienne A1 - Atwood, Larry D A1 - Fox, Caroline S A1 - Boehnke, Michael A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Erdmann, Jeanette A1 - Schunkert, Heribert A1 - Hengstenberg, Christian A1 - Stark, Klaus A1 - Lorentzon, Mattias A1 - Ohlsson, Claes A1 - Cusi, Daniele A1 - Staessen, Jan A A1 - van der Klauw, Melanie M A1 - Pramstaller, Peter P A1 - Kathiresan, Sekar A1 - Jolley, Jennifer D A1 - Ripatti, Samuli A1 - Jarvelin, Marjo-Riitta A1 - de Geus, Eco J C A1 - Boomsma, Dorret I A1 - Penninx, Brenda A1 - Wilson, James F A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - van der Harst, Pim A1 - Hamsten, Anders A1 - Watkins, Hugh A1 - Hofman, Albert A1 - Witteman, Jacqueline C A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Zillikens, M Carola A1 - Kiemeney, Lambertus A A1 - Vermeulen, Sita H A1 - Abecasis, Goncalo R A1 - Schlessinger, David A1 - Schipf, Sabine A1 - Stumvoll, Michael A1 - Tönjes, Anke A1 - Spector, Tim D A1 - North, Kari E A1 - Lettre, Guillaume A1 - McCarthy, Mark I A1 - Berndt, Sonja I A1 - Heath, Andrew C A1 - Madden, Pamela A F A1 - Nyholt, Dale R A1 - Montgomery, Grant W A1 - Martin, Nicholas G A1 - McKnight, Barbara A1 - Strachan, David P A1 - Hill, William G A1 - Snieder, Harold A1 - Ridker, Paul M A1 - Thorsteinsdottir, Unnur A1 - Stefansson, Kari A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Goddard, Michael E A1 - Visscher, Peter M KW - Alpha-Ketoglutarate-Dependent Dioxygenase FTO KW - Body Height KW - Body Mass Index KW - Co-Repressor Proteins KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Nerve Tissue Proteins KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proteins KW - Repressor Proteins AB -

There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

VL - 490 IS - 7419 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22982992?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. JF - Am J Respir Crit Care Med Y1 - 2012 A1 - Wilk, Jemma B A1 - Shrine, Nick R G A1 - Loehr, Laura R A1 - Zhao, Jing Hua A1 - Manichaikul, Ani A1 - Lopez, Lorna M A1 - Smith, Albert Vernon A1 - Heckbert, Susan R A1 - Smolonska, Joanna A1 - Tang, Wenbo A1 - Loth, Daan W A1 - Curjuric, Ivan A1 - Hui, Jennie A1 - Cho, Michael H A1 - Latourelle, Jeanne C A1 - Henry, Amanda P A1 - Aldrich, Melinda A1 - Bakke, Per A1 - Beaty, Terri H A1 - Bentley, Amy R A1 - Borecki, Ingrid B A1 - Brusselle, Guy G A1 - Burkart, Kristin M A1 - Chen, Ting-Hsu A1 - Couper, David A1 - Crapo, James D A1 - Davies, Gail A1 - Dupuis, Josée A1 - Franceschini, Nora A1 - Gulsvik, Amund A1 - Hancock, Dana B A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Imboden, Medea A1 - James, Alan L A1 - Khaw, Kay-Tee A1 - Lahousse, Lies A1 - Launer, Lenore J A1 - Litonjua, Augusto A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Lomas, David A A1 - Lumley, Thomas A1 - Marciante, Kristin D A1 - McArdle, Wendy L A1 - Meibohm, Bernd A1 - Morrison, Alanna C A1 - Musk, Arthur W A1 - Myers, Richard H A1 - North, Kari E A1 - Postma, Dirkje S A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Rochat, Thierry A1 - Rotter, Jerome I A1 - Soler Artigas, Maria A1 - Starr, John M A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Zanen, Pieter A1 - Province, Michael A A1 - Silverman, Edwin K A1 - Deary, Ian J A1 - Palmer, Lyle J A1 - Cassano, Patricia A A1 - Gudnason, Vilmundur A1 - Barr, R Graham A1 - Loos, Ruth J F A1 - Strachan, David P A1 - London, Stephanie J A1 - Boezen, H Marike A1 - Probst-Hensch, Nicole A1 - Gharib, Sina A A1 - Hall, Ian P A1 - O'Connor, George T A1 - Tobin, Martin D A1 - Stricker, Bruno H KW - Aged KW - Female KW - Forced Expiratory Volume KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Nicotinic KW - Receptors, Serotonin, 5-HT4 KW - Smoking KW - Vital Capacity AB -

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

VL - 186 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract ER - TY - JOUR T1 - Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. JF - PLoS Genet Y1 - 2012 A1 - Hancock, Dana B A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Henry, Amanda A1 - Manichaikul, Ani A1 - Ramasamy, Adaikalavan A1 - Loth, Daan W A1 - Imboden, Medea A1 - Koch, Beate A1 - McArdle, Wendy L A1 - Smith, Albert V A1 - Smolonska, Joanna A1 - Sood, Akshay A1 - Tang, Wenbo A1 - Wilk, Jemma B A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Aschard, Hugues A1 - Burkart, Kristin M A1 - Curjuric, Ivan A1 - Eijgelsheim, Mark A1 - Elliott, Paul A1 - Gu, Xiangjun A1 - Harris, Tamara B A1 - Janson, Christer A1 - Homuth, Georg A1 - Hysi, Pirro G A1 - Liu, Jason Z A1 - Loehr, Laura R A1 - Lohman, Kurt A1 - Loos, Ruth J F A1 - Manning, Alisa K A1 - Marciante, Kristin D A1 - Obeidat, Ma'en A1 - Postma, Dirkje S A1 - Aldrich, Melinda C A1 - Brusselle, Guy G A1 - Chen, Ting-Hsu A1 - Eiriksdottir, Gudny A1 - Franceschini, Nora A1 - Heinrich, Joachim A1 - Rotter, Jerome I A1 - Wijmenga, Cisca A1 - Williams, O Dale A1 - Bentley, Amy R A1 - Hofman, Albert A1 - Laurie, Cathy C A1 - Lumley, Thomas A1 - Morrison, Alanna C A1 - Joubert, Bonnie R A1 - Rivadeneira, Fernando A1 - Couper, David J A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Wjst, Matthias A1 - Wain, Louise V A1 - Vonk, Judith M A1 - Uitterlinden, André G A1 - Rochat, Thierry A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - O'Connor, George T A1 - North, Kari E A1 - Mirel, Daniel B A1 - Meibohm, Bernd A1 - Launer, Lenore J A1 - Khaw, Kay-Tee A1 - Hartikainen, Anna-Liisa A1 - Hammond, Christopher J A1 - Gläser, Sven A1 - Marchini, Jonathan A1 - Kraft, Peter A1 - Wareham, Nicholas J A1 - Völzke, Henry A1 - Stricker, Bruno H C A1 - Spector, Timothy D A1 - Probst-Hensch, Nicole M A1 - Jarvis, Deborah A1 - Jarvelin, Marjo-Riitta A1 - Heckbert, Susan R A1 - Gudnason, Vilmundur A1 - Boezen, H Marike A1 - Barr, R Graham A1 - Cassano, Patricia A A1 - Strachan, David P A1 - Fornage, Myriam A1 - Hall, Ian P A1 - Dupuis, Josée A1 - Tobin, Martin D A1 - London, Stephanie J KW - Forced Expiratory Volume KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - HLA-DQ Antigens KW - HLA-DQ beta-Chains KW - Humans KW - Lung KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Inwardly Rectifying KW - Pulmonary Disease, Chronic Obstructive KW - Receptors, Cell Surface KW - Smoking KW - SOX9 Transcription Factor KW - Vital Capacity AB -

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

VL - 8 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract ER - TY - JOUR T1 - Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. JF - Nat Genet Y1 - 2012 A1 - Scott, Robert A A1 - Lagou, Vasiliki A1 - Welch, Ryan P A1 - Wheeler, Eleanor A1 - Montasser, May E A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Strawbridge, Rona J A1 - Rehnberg, Emil A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Rasmussen-Torvik, Laura J A1 - Yengo, Loic A1 - Lecoeur, Cécile A1 - Shungin, Dmitry A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Johnson, Paul C D A1 - Jukema, J Wouter A1 - Johnson, Toby A1 - Mahajan, Anubha A1 - Verweij, Niek A1 - Thorleifsson, Gudmar A1 - Hottenga, Jouke-Jan A1 - Shah, Sonia A1 - Smith, Albert V A1 - Sennblad, Bengt A1 - Gieger, Christian A1 - Salo, Perttu A1 - Perola, Markus A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Pourcain, Beate St A1 - Wu, Ying A1 - Andrews, Jeanette S A1 - Hui, Jennie A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Horikoshi, Momoko A1 - Navarro, Pau A1 - Isaacs, Aaron A1 - O'Connell, Jeffrey R A1 - Stirrups, Kathleen A1 - Vitart, Veronique A1 - Hayward, Caroline A1 - Esko, Tõnu A1 - Mihailov, Evelin A1 - Fraser, Ross M A1 - Fall, Tove A1 - Voight, Benjamin F A1 - Raychaudhuri, Soumya A1 - Chen, Han A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Rayner, Nigel W A1 - Robertson, Neil A1 - Rybin, Denis A1 - Liu, Ching-Ti A1 - Beckmann, Jacques S A1 - Willems, Sara M A1 - Chines, Peter S A1 - Jackson, Anne U A1 - Kang, Hyun Min A1 - Stringham, Heather M A1 - Song, Kijoung A1 - Tanaka, Toshiko A1 - Peden, John F A1 - Goel, Anuj A1 - Hicks, Andrew A A1 - An, Ping A1 - Müller-Nurasyid, Martina A1 - Franco-Cereceda, Anders A1 - Folkersen, Lasse A1 - Marullo, Letizia A1 - Jansen, Hanneke A1 - Oldehinkel, Albertine J A1 - Bruinenberg, Marcel A1 - Pankow, James S A1 - North, Kari E A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Edkins, Sarah A1 - Varga, Tibor V A1 - Hallmans, Göran A1 - Oksa, Heikki A1 - Antonella, Mulas A1 - Nagaraja, Ramaiah A1 - Trompet, Stella A1 - Ford, Ian A1 - Bakker, Stephan J L A1 - Kong, Augustine A1 - Kumari, Meena A1 - Gigante, Bruna A1 - Herder, Christian A1 - Munroe, Patricia B A1 - Caulfield, Mark A1 - Antti, Jula A1 - Mangino, Massimo A1 - Small, Kerrin A1 - Miljkovic, Iva A1 - Liu, Yongmei A1 - Atalay, Mustafa A1 - Kiess, Wieland A1 - James, Alan L A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Palmer, Colin N A A1 - Doney, Alex S F A1 - Willemsen, Gonneke A1 - Smit, Johannes H A1 - Campbell, Susan A1 - Polasek, Ozren A1 - Bonnycastle, Lori L A1 - Hercberg, Serge A1 - Dimitriou, Maria A1 - Bolton, Jennifer L A1 - Fowkes, Gerard R A1 - Kovacs, Peter A1 - Lindström, Jaana A1 - Zemunik, Tatijana A1 - Bandinelli, Stefania A1 - Wild, Sarah H A1 - Basart, Hanneke V A1 - Rathmann, Wolfgang A1 - Grallert, Harald A1 - Maerz, Winfried A1 - Kleber, Marcus E A1 - Boehm, Bernhard O A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Province, Michael A A1 - Borecki, Ingrid B A1 - Hastie, Nicholas D A1 - Rudan, Igor A1 - Campbell, Harry A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Stumvoll, Michael A1 - Ferrucci, Luigi A1 - Waterworth, Dawn M A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Tuomilehto, Jaakko A1 - Watanabe, Richard M A1 - de Geus, Eco J C A1 - Penninx, Brenda W A1 - Hofman, Albert A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Wright, Alan F A1 - Hovingh, G Kees A1 - Metspalu, Andres A1 - Uusitupa, Matti A1 - Magnusson, Patrik K E A1 - Kyvik, Kirsten O A1 - Kaprio, Jaakko A1 - Price, Jackie F A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Meneton, Pierre A1 - Lind, Lars A1 - Boehnke, Michael A1 - Shuldiner, Alan R A1 - van Duijn, Cornelia M A1 - Morris, Andrew D A1 - Toenjes, Anke A1 - Peyser, Patricia A A1 - Beilby, John P A1 - Körner, Antje A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Adair, Linda S A1 - Smith, George Davey A1 - Spector, Tim D A1 - Illig, Thomas A1 - de Faire, Ulf A1 - Hamsten, Anders A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Hingorani, Aroon A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Boomsma, Dorret I A1 - Stefansson, Kari A1 - van der Harst, Pim A1 - Dupuis, Josée A1 - Pedersen, Nancy L A1 - Sattar, Naveed A1 - Harris, Tamara B A1 - Cucca, Francesco A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Mohlke, Karen L A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Pouta, Anneli A1 - Jarvelin, Marjo-Riitta A1 - Wareham, Nicholas J A1 - Bouatia-Naji, Nabila A1 - McCarthy, Mark I A1 - Franks, Paul W A1 - Meigs, James B A1 - Teslovich, Tanya M A1 - Florez, Jose C A1 - Langenberg, Claudia A1 - Ingelsson, Erik A1 - Prokopenko, Inga A1 - Barroso, Inês KW - Adult KW - Animals KW - Blood Glucose KW - Fasting KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Insulin KW - Male KW - Metabolic Networks and Pathways KW - Mice KW - Osmolar Concentration KW - Quantitative Trait Loci AB -

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

VL - 44 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract ER - TY - JOUR T1 - Lipid-related markers and cardiovascular disease prediction. JF - JAMA Y1 - 2012 A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Pennells, Lisa A1 - Kaptoge, Stephen A1 - Caslake, Muriel A1 - Thompson, Alexander A1 - Butterworth, Adam S A1 - Sarwar, Nadeem A1 - Wormser, David A1 - Saleheen, Danish A1 - Ballantyne, Christie M A1 - Psaty, Bruce M A1 - Sundström, Johan A1 - Ridker, Paul M A1 - Nagel, Dorothea A1 - Gillum, Richard F A1 - Ford, Ian A1 - Ducimetiere, Pierre A1 - Kiechl, Stefan A1 - Koenig, Wolfgang A1 - Dullaart, Robin P F A1 - Assmann, Gerd A1 - D'Agostino, Ralph B A1 - Dagenais, Gilles R A1 - Cooper, Jackie A A1 - Kromhout, Daan A1 - Onat, Altan A1 - Tipping, Robert W A1 - Gómez-de-la-Cámara, Agustín A1 - Rosengren, Annika A1 - Sutherland, Susan E A1 - Gallacher, John A1 - Fowkes, F Gerry R A1 - Casiglia, Edoardo A1 - Hofman, Albert A1 - Salomaa, Veikko A1 - Barrett-Connor, Elizabeth A1 - Clarke, Robert A1 - Brunner, Eric A1 - Jukema, J Wouter A1 - Simons, Leon A A1 - Sandhu, Manjinder A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Howard, William J A1 - Nordestgaard, Børge G A1 - Wood, Angela M A1 - Thompson, Simon G A1 - Boekholdt, S Matthijs A1 - Sattar, Naveed A1 - Packard, Chris A1 - Gudnason, Vilmundur A1 - Danesh, John KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cohort Studies KW - Female KW - Humans KW - Lipoproteins KW - Male KW - Middle Aged KW - Risk Assessment AB -

CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.

OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.

DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).

MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.

RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.

CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

VL - 307 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22797450?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 - 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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 variants associated with plasma triglycerides and risk for coronary artery disease. JF - Nat Genet Y1 - 2013 A1 - Do, Ron A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Gao, Chi A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Eyjolfsson, Gudmundur Ingi A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Altshuler, David A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R A1 - Daly, Mark J A1 - Neale, Benjamin M A1 - Kathiresan, Sekar KW - Biological Transport KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Triglycerides AB -

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

VL - 45 IS - 11 ER - TY - JOUR T1 - Discovery and refinement of loci associated with lipid levels. JF - Nat Genet Y1 - 2013 A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Do, Ron A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Ingi Eyjolfsson, Gudmundur A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Kathiresan, Sekar A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R KW - African Continental Ancestry Group KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipids KW - Triglycerides AB -

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

VL - 45 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. JF - Nat Genet Y1 - 2013 A1 - Köttgen, Anna A1 - Albrecht, Eva A1 - Teumer, Alexander A1 - Vitart, Veronique A1 - Krumsiek, Jan A1 - Hundertmark, Claudia A1 - Pistis, Giorgio A1 - Ruggiero, Daniela A1 - O'Seaghdha, Conall M A1 - Haller, Toomas A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Johnson, Andrew D A1 - Kutalik, Zoltán A1 - Smith, Albert V A1 - Shi, Julia A1 - Struchalin, Maksim A1 - Middelberg, Rita P S A1 - Brown, Morris J A1 - Gaffo, Angelo L A1 - Pirastu, Nicola A1 - Li, Guo A1 - Hayward, Caroline A1 - Zemunik, Tatijana A1 - Huffman, Jennifer A1 - Yengo, Loic A1 - Zhao, Jing Hua A1 - Demirkan, Ayse A1 - Feitosa, Mary F A1 - Liu, Xuan A1 - Malerba, Giovanni A1 - Lopez, Lorna M A1 - van der Harst, Pim A1 - Li, Xinzhong A1 - Kleber, Marcus E A1 - Hicks, Andrew A A1 - Nolte, Ilja M A1 - Johansson, Asa A1 - Murgia, Federico A1 - Wild, Sarah H A1 - Bakker, Stephan J L A1 - Peden, John F A1 - Dehghan, Abbas A1 - Steri, Maristella A1 - Tenesa, Albert A1 - Lagou, Vasiliki A1 - Salo, Perttu A1 - Mangino, Massimo A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Woodward, Owen M A1 - Okada, Yukinori A1 - Tin, Adrienne A1 - Müller, Christian A1 - Oldmeadow, Christopher A1 - Putku, Margus A1 - Czamara, Darina A1 - Kraft, Peter A1 - Frogheri, Laura A1 - Thun, Gian Andri A1 - Grotevendt, Anne A1 - Gislason, Gauti Kjartan A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - McArdle, Patrick A1 - Shuldiner, Alan R A1 - Boerwinkle, Eric A1 - Coresh, Josef A1 - Schmidt, Helena A1 - Schallert, Michael A1 - Martin, Nicholas G A1 - Montgomery, Grant W A1 - Kubo, Michiaki A1 - Nakamura, Yusuke A1 - Tanaka, Toshihiro A1 - Munroe, Patricia B A1 - Samani, Nilesh J A1 - Jacobs, David R A1 - Liu, Kiang A1 - D'Adamo, Pio A1 - Ulivi, Sheila A1 - Rotter, Jerome I A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Campbell, Susan A1 - Devuyst, Olivier A1 - Navarro, Pau A1 - Kolcic, Ivana A1 - Hastie, Nicholas A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Esko, Tõnu A1 - Salumets, Andres A1 - Khaw, Kay Tee A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Isaacs, Aaron A1 - Kraja, Aldi A1 - Zhang, Qunyuan A1 - Wild, Philipp S A1 - Scott, Rodney J A1 - Holliday, Elizabeth G A1 - Org, Elin A1 - Viigimaa, Margus A1 - Bandinelli, Stefania A1 - Metter, Jeffrey E A1 - Lupo, Antonio A1 - Trabetti, Elisabetta A1 - Sorice, Rossella A1 - Döring, Angela A1 - Lattka, Eva A1 - Strauch, Konstantin A1 - Theis, Fabian A1 - Waldenberger, Melanie A1 - Wichmann, H-Erich A1 - Davies, Gail A1 - Gow, Alan J A1 - Bruinenberg, Marcel A1 - Stolk, Ronald P A1 - Kooner, Jaspal S A1 - Zhang, Weihua A1 - Winkelmann, Bernhard R A1 - Boehm, Bernhard O A1 - Lucae, Susanne A1 - Penninx, Brenda W A1 - Smit, Johannes H A1 - Curhan, Gary A1 - Mudgal, Poorva A1 - Plenge, Robert M A1 - Portas, Laura A1 - Persico, Ivana A1 - Kirin, Mirna A1 - Wilson, James F A1 - Mateo Leach, Irene A1 - van Gilst, Wiek H A1 - Goel, Anuj A1 - Ongen, Halit A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Imboden, Medea A1 - von Eckardstein, Arnold A1 - Cucca, Francesco A1 - Nagaraja, Ramaiah A1 - Piras, Maria Grazia A1 - Nauck, Matthias A1 - Schurmann, Claudia A1 - Budde, Kathrin A1 - Ernst, Florian A1 - Farrington, Susan M A1 - Theodoratou, Evropi A1 - Prokopenko, Inga A1 - Stumvoll, Michael A1 - Jula, Antti A1 - Perola, Markus A1 - Salomaa, Veikko A1 - Shin, So-Youn A1 - Spector, Tim D A1 - Sala, Cinzia A1 - Ridker, Paul M A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Hengstenberg, Christian A1 - Nelson, Christopher P A1 - Meschia, James F A1 - Nalls, Michael A A1 - Sharma, Pankaj A1 - Singleton, Andrew B A1 - Kamatani, Naoyuki A1 - Zeller, Tanja A1 - Burnier, Michel A1 - Attia, John A1 - Laan, Maris A1 - Klopp, Norman A1 - Hillege, Hans L A1 - Kloiber, Stefan A1 - Choi, Hyon A1 - Pirastu, Mario A1 - Tore, Silvia A1 - Probst-Hensch, Nicole M A1 - Völzke, Henry A1 - Gudnason, Vilmundur A1 - Parsa, Afshin A1 - Schmidt, Reinhold A1 - Whitfield, John B A1 - Fornage, Myriam A1 - Gasparini, Paolo A1 - Siscovick, David S A1 - Polasek, Ozren A1 - Campbell, Harry A1 - Rudan, Igor A1 - Bouatia-Naji, Nabila A1 - Metspalu, Andres A1 - Loos, Ruth J F A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid B A1 - Ferrucci, Luigi A1 - Gambaro, Giovanni A1 - Deary, Ian J A1 - Wolffenbuttel, Bruce H R A1 - Chambers, John C A1 - März, Winfried A1 - Pramstaller, Peter P A1 - Snieder, Harold A1 - Gyllensten, Ulf A1 - Wright, Alan F A1 - Navis, Gerjan A1 - Watkins, Hugh A1 - Witteman, Jacqueline C M A1 - Sanna, Serena A1 - Schipf, Sabine A1 - Dunlop, Malcolm G A1 - Tönjes, Anke A1 - Ripatti, Samuli A1 - Soranzo, Nicole A1 - Toniolo, Daniela A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Kao, W H Linda A1 - Ciullo, Marina A1 - Fox, Caroline S A1 - Caulfield, Mark A1 - Bochud, Murielle A1 - Gieger, Christian KW - Analysis of Variance KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Glucose KW - Gout KW - Humans KW - Inhibins KW - Polymorphism, Single Nucleotide KW - Signal Transduction KW - Uric Acid AB -

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

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23263486?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. JF - Nat Genet Y1 - 2013 A1 - Berndt, Sonja I A1 - Gustafsson, Stefan A1 - Mägi, Reedik A1 - Ganna, Andrea A1 - Wheeler, Eleanor A1 - Feitosa, Mary F A1 - Justice, Anne E A1 - Monda, Keri L A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Esko, Tõnu A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gentilini, Davide A1 - Jackson, Anne U A1 - Luan, Jian'an A1 - Randall, Joshua C A1 - Vedantam, Sailaja A1 - Willer, Cristen J A1 - Winkler, Thomas W A1 - Wood, Andrew R A1 - Workalemahu, Tsegaselassie A1 - Hu, Yi-Juan A1 - Lee, Sang Hong A1 - Liang, Liming A1 - Lin, Dan-Yu A1 - Min, Josine L A1 - Neale, Benjamin M A1 - Thorleifsson, Gudmar A1 - Yang, Jian A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - den Heijer, Martin A1 - Eklund, Niina A1 - Fischer, Krista A1 - Goel, Anuj A1 - Hottenga, Jouke-Jan A1 - Huffman, Jennifer E A1 - Jarick, Ivonne A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kanoni, Stavroula A1 - Kleber, Marcus E A1 - König, Inke R A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lamina, Claudia A1 - Lecoeur, Cécile A1 - Li, Guo A1 - Mangino, Massimo A1 - McArdle, Wendy L A1 - Medina-Gómez, Carolina A1 - Müller-Nurasyid, Martina A1 - Ngwa, Julius S A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Pechlivanis, Sonali A1 - Perola, Markus A1 - Peters, Marjolein J A1 - Preuss, Michael A1 - Rose, Lynda M A1 - Shi, Jianxin A1 - Shungin, Dmitry A1 - Smith, Albert Vernon A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Teumer, Alexander A1 - Trip, Mieke D A1 - Tyrer, Jonathan A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Waite, Lindsay L A1 - Zhao, Jing Hua A1 - Absher, Devin A1 - Asselbergs, Folkert W A1 - Atalay, Mustafa A1 - Attwood, Antony P A1 - Balmforth, Anthony J A1 - Basart, Hanneke A1 - Beilby, John A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chasman, Daniel I A1 - Chines, Peter S A1 - Collins, Francis S A1 - Connell, John M A1 - Cookson, William O A1 - de Faire, Ulf A1 - de Vegt, Femmie A1 - Dei, Mariano A1 - Dimitriou, Maria A1 - Edkins, Sarah A1 - Estrada, Karol A1 - Evans, David M A1 - Farrall, Martin A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Franke, Lude A1 - Frau, Francesca A1 - Gejman, Pablo V A1 - Grallert, Harald A1 - Grönberg, Henrik A1 - Gudnason, Vilmundur A1 - Hall, Alistair S A1 - Hall, Per A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Heath, Andrew C A1 - Hebebrand, Johannes A1 - Homuth, Georg A1 - Hu, Frank B A1 - Hunt, Sarah E A1 - Hyppönen, Elina A1 - Iribarren, Carlos A1 - Jacobs, Kevin B A1 - Jansson, John-Olov A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Khaw, Kay-Tee A1 - Kivimaki, Mika A1 - Koenig, Wolfgang A1 - Kraja, Aldi T A1 - Kumari, Meena A1 - Kuulasmaa, Kari A1 - Kuusisto, Johanna A1 - Laitinen, Jaana H A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lind, Lars A1 - Lindström, Jaana A1 - Liu, Jianjun A1 - Liuzzi, Antonio A1 - Lokki, Marja-Liisa A1 - Lorentzon, Mattias A1 - Madden, Pamela A A1 - Magnusson, Patrik K A1 - Manunta, Paolo A1 - Marek, Diana A1 - März, Winfried A1 - Mateo Leach, Irene A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Montgomery, Grant W A1 - Mooser, Vincent A1 - Mühleisen, Thomas W A1 - Munroe, Patricia B A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Navis, Gerjan A1 - Nicholson, George A1 - Nohr, Ellen A A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Palmer, Colin N A A1 - Palotie, Aarno A1 - Peden, John F A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Prokopenko, Inga A1 - Pütter, Carolin A1 - Radhakrishnan, Aparna A1 - Raitakari, Olli A1 - Rendon, Augusto A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Saaristo, Timo E A1 - Sambrook, Jennifer G A1 - Sanders, Alan R A1 - Sanna, Serena A1 - Saramies, Jouko A1 - Schipf, Sabine A1 - Schreiber, Stefan A1 - Schunkert, Heribert A1 - Shin, So-Youn A1 - Signorini, Stefano A1 - Sinisalo, Juha A1 - Skrobek, Boris A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Stark, Klaus A1 - Stephens, Jonathan C A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Stumvoll, Michael A1 - Swift, Amy J A1 - Theodoraki, Eirini V A1 - Thorand, Barbara A1 - Trégouët, David-Alexandre A1 - Tremoli, Elena A1 - van der Klauw, Melanie M A1 - van Meurs, Joyce B J A1 - Vermeulen, Sita H A1 - Viikari, Jorma A1 - Virtamo, Jarmo A1 - Vitart, Veronique A1 - Waeber, Gérard A1 - Wang, Zhaoming A1 - Widen, Elisabeth A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Winkelmann, Bernhard R A1 - Witteman, Jacqueline C M A1 - Wolffenbuttel, Bruce H R A1 - Wong, Andrew A1 - Wright, Alan F A1 - Zillikens, M Carola A1 - Amouyel, Philippe A1 - Boehm, Bernhard O A1 - Boerwinkle, Eric A1 - Boomsma, Dorret I A1 - Caulfield, Mark J A1 - Chanock, Stephen J A1 - Cupples, L Adrienne A1 - Cusi, Daniele A1 - Dedoussis, George V A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hengstenberg, Christian A1 - Hicks, Andrew A A1 - Hingorani, Aroon A1 - Hinney, Anke A1 - Hofman, Albert A1 - Hovingh, Kees G A1 - Hveem, Kristian A1 - Illig, Thomas A1 - Jarvelin, Marjo-Riitta A1 - Jöckel, Karl-Heinz A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kiemeney, Lambertus A A1 - Kuh, Diana A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Levinson, Douglas F A1 - Martin, Nicholas G A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nieminen, Markku S A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Ouwehand, Willem H A1 - Palmer, Lyle J A1 - Penninx, Brenda A1 - Power, Chris A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Qi, Lu A1 - Rauramaa, Rainer A1 - Ridker, Paul M A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Tönjes, Anke A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - van der Harst, Pim A1 - Vollenweider, Peter A1 - Wallaschofski, Henri A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Abecasis, Goncalo R A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunian, Talin A1 - Heid, Iris M A1 - Hunter, David A1 - Kaplan, Robert C A1 - Karpe, Fredrik A1 - Moffatt, Miriam F A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Pawitan, Yudi A1 - Schadt, Eric E A1 - Schlessinger, David A1 - Steinthorsdottir, Valgerdur A1 - Strachan, David P A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Visscher, Peter M A1 - Di Blasio, Anna Maria A1 - Hirschhorn, Joel N A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Meyre, David A1 - Scherag, Andre A1 - McCarthy, Mark I A1 - Speliotes, Elizabeth K A1 - North, Kari E A1 - Loos, Ruth J F A1 - Ingelsson, Erik KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Case-Control Studies KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Meta-Analysis as Topic KW - Obesity KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Waist-Hip Ratio AB -

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.

VL - 45 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23563607?dopt=Abstract ER - TY - JOUR T1 - Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake. JF - Am J Clin Nutr Y1 - 2013 A1 - Tanaka, Toshiko A1 - Ngwa, Julius S A1 - van Rooij, Frank J A A1 - Zillikens, M Carola A1 - Wojczynski, Mary K A1 - Frazier-Wood, Alexis C A1 - Houston, Denise K A1 - Kanoni, Stavroula A1 - Lemaitre, Rozenn N A1 - Luan, Jian'an A1 - Mikkilä, Vera A1 - Renstrom, Frida A1 - Sonestedt, Emily A1 - Zhao, Jing Hua A1 - Chu, Audrey Y A1 - Qi, Lu A1 - Chasman, Daniel I A1 - de Oliveira Otto, Marcia C A1 - Dhurandhar, Emily J A1 - Feitosa, Mary F A1 - Johansson, Ingegerd A1 - Khaw, Kay-Tee A1 - Lohman, Kurt K A1 - Manichaikul, Ani A1 - McKeown, Nicola M A1 - Mozaffarian, Dariush A1 - Singleton, Andrew A1 - Stirrups, Kathleen A1 - Viikari, Jorma A1 - Ye, Zheng A1 - Bandinelli, Stefania A1 - Barroso, Inês A1 - Deloukas, Panos A1 - Forouhi, Nita G A1 - Hofman, Albert A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - North, Kari E A1 - Dimitriou, Maria A1 - Hallmans, Göran A1 - Kähönen, Mika A1 - Langenberg, Claudia A1 - Ordovas, Jose M A1 - Uitterlinden, André G A1 - Hu, Frank B A1 - Kalafati, Ioanna-Panagiota A1 - Raitakari, Olli A1 - Franco, Oscar H A1 - Johnson, Andrew A1 - Emilsson, Valur A1 - Schrack, Jennifer A A1 - Semba, Richard D A1 - Siscovick, David S A1 - Arnett, Donna K A1 - Borecki, Ingrid B A1 - Franks, Paul W A1 - Kritchevsky, Stephen B A1 - Lehtimäki, Terho A1 - Loos, Ruth J F A1 - Orho-Melander, Marju A1 - Rotter, Jerome I A1 - Wareham, Nicholas J A1 - Witteman, Jacqueline C M A1 - Ferrucci, Luigi A1 - Dedoussis, George A1 - Cupples, L Adrienne A1 - Nettleton, Jennifer A KW - Alleles KW - Atherosclerosis KW - Body Mass Index KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Fibroblast Growth Factors KW - Follow-Up Studies KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Life Style KW - Obesity KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Quantitative Trait Loci KW - Surveys and Questionnaires AB -

BACKGROUND: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.

OBJECTIVE: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.

DESIGN: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.

RESULTS: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10(-8)) and lower fat (β ± SE: -0.21 ± 0.04%; P = 1.57 × 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)-increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10(-10)), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10(-7)).

CONCLUSION: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

VL - 97 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23636237?dopt=Abstract ER - TY - JOUR T1 - Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. JF - Nat Genet Y1 - 2013 A1 - den Hoed, Marcel A1 - Eijgelsheim, Mark A1 - Esko, Tõnu A1 - Brundel, Bianca J J M A1 - Peal, David S A1 - Evans, David M A1 - Nolte, Ilja M A1 - Segrè, Ayellet V A1 - Holm, Hilma A1 - Handsaker, Robert E A1 - Westra, Harm-Jan A1 - Johnson, Toby A1 - Isaacs, Aaron A1 - Yang, Jian A1 - Lundby, Alicia A1 - Zhao, Jing Hua A1 - Kim, Young Jin A1 - Go, Min Jin A1 - Almgren, Peter A1 - Bochud, Murielle A1 - Boucher, Gabrielle A1 - Cornelis, Marilyn C A1 - Gudbjartsson, Daniel A1 - Hadley, David A1 - van der Harst, Pim A1 - Hayward, Caroline A1 - den Heijer, Martin A1 - Igl, Wilmar A1 - Jackson, Anne U A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Kemp, John P A1 - Kristiansson, Kati A1 - Ladenvall, Claes A1 - Lorentzon, Mattias A1 - Montasser, May E A1 - Njajou, Omer T A1 - O'Reilly, Paul F A1 - Padmanabhan, Sandosh A1 - St Pourcain, Beate A1 - Rankinen, Tuomo A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - Timpson, Nicholas J A1 - Vitart, Veronique A1 - Waite, Lindsay A1 - Wheeler, William A1 - Zhang, Weihua A1 - Draisma, Harmen H M A1 - Feitosa, Mary F A1 - Kerr, Kathleen F A1 - Lind, Penelope A A1 - Mihailov, Evelin A1 - Onland-Moret, N Charlotte A1 - Song, Ci A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Yengo, Loic A1 - Absher, Devin A1 - Albert, Christine M A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - de Bakker, Paul I W A1 - Balkau, Beverley A1 - Barlassina, Cristina A1 - Benaglio, Paola A1 - Bis, Joshua C A1 - Bouatia-Naji, Nabila A1 - Brage, Søren A1 - Chanock, Stephen J A1 - Chines, Peter S A1 - Chung, Mina A1 - Darbar, Dawood A1 - Dina, Christian A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Felix, Stephan B A1 - Fischer, Krista A1 - Fuchsberger, Christian A1 - de Geus, Eco J C A1 - Goyette, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Havulinna, Aki S A1 - Heckbert, Susan R A1 - Hicks, Andrew A A1 - Hofman, Albert A1 - Holewijn, Suzanne A1 - Hoogstra-Berends, Femke A1 - Hottenga, Jouke-Jan A1 - Jensen, Majken K A1 - Johansson, Asa A1 - Junttila, Juhani A1 - Kääb, Stefan A1 - Kanon, Bart A1 - Ketkar, Shamika A1 - Khaw, Kay-Tee A1 - Knowles, Joshua W A1 - Kooner, Angrad S A1 - Kors, Jan A A1 - Kumari, Meena A1 - Milani, Lili A1 - Laiho, Päivi A1 - Lakatta, Edward G A1 - Langenberg, Claudia A1 - Leusink, Maarten A1 - Liu, Yongmei A1 - Luben, Robert N A1 - Lunetta, Kathryn L A1 - Lynch, Stacey N A1 - Markus, Marcello R P A1 - Marques-Vidal, Pedro A1 - Mateo Leach, Irene A1 - McArdle, Wendy L A1 - McCarroll, Steven A A1 - Medland, Sarah E A1 - Miller, Kathryn A A1 - Montgomery, Grant W A1 - Morrison, Alanna C A1 - Müller-Nurasyid, Martina A1 - Navarro, Pau A1 - Nelis, Mari A1 - O'Connell, Jeffrey R A1 - O'Donnell, Christopher J A1 - Ong, Ken K A1 - Newman, Anne B A1 - Peters, Annette A1 - Polasek, Ozren A1 - Pouta, Anneli A1 - Pramstaller, Peter P A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Ring, Susan M A1 - Rossin, Elizabeth J A1 - Rudan, Diana A1 - Sanna, Serena A1 - Scott, Robert A A1 - Sehmi, Jaban S A1 - Sharp, Stephen A1 - Shin, Jordan T A1 - Singleton, Andrew B A1 - Smith, Albert V A1 - Soranzo, Nicole A1 - Spector, Tim D A1 - Stewart, Chip A1 - Stringham, Heather M A1 - Tarasov, Kirill V A1 - Uitterlinden, André G A1 - Vandenput, Liesbeth A1 - Hwang, Shih-Jen A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Wong, Andrew A1 - Wong, Quenna A1 - Jamshidi, Yalda A1 - Zitting, Paavo A1 - Boer, Jolanda M A A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Ekelund, Ulf A1 - Forouhi, Nita G A1 - Froguel, Philippe A1 - Hingorani, Aroon A1 - Ingelsson, Erik A1 - Kivimaki, Mika A1 - Kronmal, Richard A A1 - Kuh, Diana A1 - Lind, Lars A1 - Martin, Nicholas G A1 - Oostra, Ben A A1 - Pedersen, Nancy L A1 - Quertermous, Thomas A1 - Rotter, Jerome I A1 - van der Schouw, Yvonne T A1 - Verschuren, W M Monique A1 - Walker, Mark A1 - Albanes, Demetrius A1 - Arnar, David O A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Boehnke, Michael A1 - de Boer, Rudolf A A1 - Bouchard, Claude A1 - Caulfield, W L Mark A1 - Chambers, John C A1 - Curhan, Gary A1 - Cusi, Daniele A1 - Eriksson, Johan A1 - Ferrucci, Luigi A1 - van Gilst, Wiek H A1 - Glorioso, Nicola A1 - de Graaf, Jacqueline A1 - Groop, Leif A1 - Gyllensten, Ulf A1 - Hsueh, Wen-Chi A1 - Hu, Frank B A1 - Huikuri, Heikki V A1 - Hunter, David J A1 - Iribarren, Carlos A1 - Isomaa, Bo A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kiemeney, Lambertus A A1 - van der Klauw, Melanie M A1 - Kooner, Jaspal S A1 - Kraft, Peter A1 - Iacoviello, Licia A1 - Lehtimäki, Terho A1 - Lokki, Marja-Liisa L A1 - Mitchell, Braxton D A1 - Navis, Gerjan A1 - Nieminen, Markku S A1 - Ohlsson, Claes A1 - Poulter, Neil R A1 - Qi, Lu A1 - Raitakari, Olli T A1 - Rimm, Eric B A1 - Rioux, John D A1 - Rizzi, Federica A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Sever, Peter S A1 - Shields, Denis C A1 - Shuldiner, Alan R A1 - Sinisalo, Juha A1 - Stanton, Alice V A1 - Stolk, Ronald P A1 - Strachan, David P A1 - Tardif, Jean-Claude A1 - Thorsteinsdottir, Unnur A1 - Tuomilehto, Jaako A1 - van Veldhuisen, Dirk J A1 - Virtamo, Jarmo A1 - Viikari, Jorma A1 - Vollenweider, Peter A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Cho, Yoon Shin A1 - Olsen, Jesper V A1 - Visscher, Peter M A1 - Willer, Cristen A1 - Franke, Lude A1 - Erdmann, Jeanette A1 - Thompson, John R A1 - Pfeufer, Arne A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Ellinor, Patrick T A1 - Stricker, Bruno H Ch A1 - Metspalu, Andres A1 - Perola, Markus A1 - Beckmann, Jacques S A1 - Smith, George Davey A1 - Stefansson, Kari A1 - Wareham, Nicholas J A1 - Munroe, Patricia B A1 - Sibon, Ody C M A1 - Milan, David J A1 - Snieder, Harold A1 - Samani, Nilesh J A1 - Loos, Ruth J F KW - Animals KW - Arrhythmias, Cardiac KW - Gene Frequency KW - Genetic Loci KW - Genome-Wide Association Study KW - Heart Conduction System KW - Heart Rate KW - Humans KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

VL - 45 IS - 6 ER - TY - JOUR T1 - Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. JF - PLoS Genet Y1 - 2013 A1 - Randall, Joshua C A1 - Winkler, Thomas W A1 - Kutalik, Zoltán A1 - Berndt, Sonja I A1 - Jackson, Anne U A1 - Monda, Keri L A1 - Kilpeläinen, Tuomas O A1 - Esko, Tõnu A1 - Mägi, Reedik A1 - Li, Shengxu A1 - Workalemahu, Tsegaselassie A1 - Feitosa, Mary F A1 - Croteau-Chonka, Damien C A1 - Day, Felix R A1 - Fall, Tove A1 - Ferreira, Teresa A1 - Gustafsson, Stefan A1 - Locke, Adam E A1 - Mathieson, Iain A1 - Scherag, Andre A1 - Vedantam, Sailaja A1 - Wood, Andrew R A1 - Liang, Liming A1 - Steinthorsdottir, Valgerdur A1 - Thorleifsson, Gudmar A1 - Dermitzakis, Emmanouil T A1 - Dimas, Antigone S A1 - Karpe, Fredrik A1 - Min, Josine L A1 - Nicholson, George A1 - Clegg, Deborah J A1 - Person, Thomas A1 - Krohn, Jon P A1 - Bauer, Sabrina A1 - Buechler, Christa A1 - Eisinger, Kristina A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Hottenga, Jouke-Jan A1 - Prokopenko, Inga A1 - Waite, Lindsay L A1 - Harris, Tamara B A1 - Smith, Albert Vernon A1 - Shuldiner, Alan R A1 - McArdle, Wendy L A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Grönberg, Henrik A1 - Chen, Yii-Der Ida A1 - Li, Guo A1 - Beckmann, Jacques S A1 - Johnson, Toby A1 - Thorsteinsdottir, Unnur A1 - Teder-Laving, Maris A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Oostra, Ben A A1 - Kraja, Aldi T A1 - Province, Michael A A1 - Cupples, L Adrienne A1 - Heard-Costa, Nancy L A1 - Kaprio, Jaakko A1 - Ripatti, Samuli A1 - Surakka, Ida A1 - Collins, Francis S A1 - Saramies, Jouko A1 - Tuomilehto, Jaakko A1 - Jula, Antti A1 - Salomaa, Veikko A1 - Erdmann, Jeanette A1 - Hengstenberg, Christian A1 - Loley, Christina A1 - Schunkert, Heribert A1 - Lamina, Claudia A1 - Wichmann, H Erich A1 - Albrecht, Eva A1 - Gieger, Christian A1 - Hicks, Andrew A A1 - Johansson, Asa A1 - Pramstaller, Peter P A1 - Kathiresan, Sekar A1 - Speliotes, Elizabeth K A1 - Penninx, Brenda A1 - Hartikainen, Anna-Liisa A1 - Jarvelin, Marjo-Riitta A1 - Gyllensten, Ulf A1 - Boomsma, Dorret I A1 - Campbell, Harry A1 - Wilson, James F A1 - Chanock, Stephen J A1 - Farrall, Martin A1 - Goel, Anuj A1 - Medina-Gómez, Carolina A1 - Rivadeneira, Fernando A1 - Estrada, Karol A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Zillikens, M Carola A1 - den Heijer, Martin A1 - Kiemeney, Lambertus A A1 - Maschio, Andrea A1 - Hall, Per A1 - Tyrer, Jonathan A1 - Teumer, Alexander A1 - Völzke, Henry A1 - Kovacs, Peter A1 - Tönjes, Anke A1 - Mangino, Massimo A1 - Spector, Tim D A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Hall, Alistair S A1 - Samani, Nilesh J A1 - Attwood, Antony Paul A1 - Sambrook, Jennifer G A1 - Hung, Joseph A1 - Palmer, Lyle J A1 - Lokki, Marja-Liisa A1 - Sinisalo, Juha A1 - Boucher, Gabrielle A1 - Huikuri, Heikki A1 - Lorentzon, Mattias A1 - Ohlsson, Claes A1 - Eklund, Niina A1 - Eriksson, Johan G A1 - Barlassina, Cristina A1 - Rivolta, Carlo A1 - Nolte, Ilja M A1 - Snieder, Harold A1 - van der Klauw, Melanie M A1 - van Vliet-Ostaptchouk, Jana V A1 - Gejman, Pablo V A1 - Shi, Jianxin A1 - Jacobs, Kevin B A1 - Wang, Zhaoming A1 - Bakker, Stephan J L A1 - Mateo Leach, Irene A1 - Navis, Gerjan A1 - van der Harst, Pim A1 - Martin, Nicholas G A1 - Medland, Sarah E A1 - Montgomery, Grant W A1 - Yang, Jian A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Lehtimäki, Terho A1 - Raitakari, Olli A1 - Absher, Devin A1 - Iribarren, Carlos A1 - Basart, Hanneke A1 - Hovingh, Kees G A1 - Hyppönen, Elina A1 - Power, Chris A1 - Anderson, Denise A1 - Beilby, John P A1 - Hui, Jennie A1 - Jolley, Jennifer A1 - Sager, Hendrik A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Kristiansson, Kati A1 - Perola, Markus A1 - Lindström, Jaana A1 - Swift, Amy J A1 - Uusitupa, Matti A1 - Atalay, Mustafa A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Bolton, Jennifer L A1 - Fowkes, Gerry A1 - Fraser, Ross M A1 - Price, Jackie F A1 - Fischer, Krista A1 - Krjutå Kov, Kaarel A1 - Metspalu, Andres A1 - Mihailov, Evelin A1 - Langenberg, Claudia A1 - Luan, Jian'an A1 - Ong, Ken K A1 - Chines, Peter S A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Edkins, Sarah A1 - Franks, Paul W A1 - Hallmans, Göran A1 - Shungin, Dmitry A1 - Morris, Andrew David A1 - Palmer, Colin N A A1 - Erbel, Raimund A1 - Moebus, Susanne A1 - Nöthen, Markus M A1 - Pechlivanis, Sonali A1 - Hveem, Kristian A1 - Narisu, Narisu A1 - Hamsten, Anders A1 - Humphries, Steve E A1 - Strawbridge, Rona J A1 - Tremoli, Elena A1 - Grallert, Harald A1 - Thorand, Barbara A1 - Illig, Thomas A1 - Koenig, Wolfgang A1 - Müller-Nurasyid, Martina A1 - Peters, Annette A1 - Boehm, Bernhard O A1 - Kleber, Marcus E A1 - März, Winfried A1 - Winkelmann, Bernhard R A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Arveiler, Dominique A1 - Cesana, Giancarlo A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Yarnell, John W G A1 - Kuh, Diana A1 - Wong, Andrew A1 - Lind, Lars A1 - de Faire, Ulf A1 - Gigante, Bruna A1 - Magnusson, Patrik K E A1 - Pedersen, Nancy L A1 - Dedoussis, George A1 - Dimitriou, Maria A1 - Kolovou, Genovefa A1 - Kanoni, Stavroula A1 - Stirrups, Kathleen A1 - Bonnycastle, Lori L A1 - Njølstad, Inger A1 - Wilsgaard, Tom A1 - Ganna, Andrea A1 - Rehnberg, Emil A1 - Hingorani, Aroon A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Assimes, Themistocles L A1 - Barroso, Inês A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - Fox, Caroline S A1 - Frayling, Timothy A1 - Groop, Leif C A1 - Haritunians, Talin A1 - Hunter, David A1 - Ingelsson, Erik A1 - Kaplan, Robert A1 - Mohlke, Karen L A1 - O'Connell, Jeffrey R A1 - Schlessinger, David A1 - Strachan, David P A1 - Stefansson, Kari A1 - van Duijn, Cornelia M A1 - Abecasis, Goncalo R A1 - McCarthy, Mark I A1 - Hirschhorn, Joel N A1 - Qi, Lu A1 - Loos, Ruth J F A1 - Lindgren, Cecilia M A1 - North, Kari E A1 - Heid, Iris M KW - Anthropometry KW - Body Height KW - Body Mass Index KW - Body Weight KW - Body Weights and Measures KW - Female KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Male KW - Polymorphism, Single Nucleotide KW - Sex Characteristics KW - Waist Circumference KW - Waist-Hip Ratio AB -

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

VL - 9 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23754948?dopt=Abstract ER - TY - JOUR T1 - Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. JF - BMJ Y1 - 2014 A1 - Holmes, Michael V A1 - Dale, Caroline E A1 - Zuccolo, Luisa A1 - Silverwood, Richard J A1 - Guo, Yiran A1 - Ye, Zheng A1 - Prieto-Merino, David A1 - Dehghan, Abbas A1 - Trompet, Stella A1 - Wong, Andrew A1 - Cavadino, Alana A1 - Drogan, Dagmar A1 - Padmanabhan, Sandosh A1 - Li, Shanshan A1 - Yesupriya, Ajay A1 - Leusink, Maarten A1 - Sundström, Johan A1 - Hubacek, Jaroslav A A1 - Pikhart, Hynek A1 - Swerdlow, Daniel I A1 - Panayiotou, Andrie G A1 - Borinskaya, Svetlana A A1 - Finan, Chris A1 - Shah, Sonia A1 - Kuchenbaecker, Karoline B A1 - Shah, Tina A1 - Engmann, Jorgen A1 - Folkersen, Lasse A1 - Eriksson, Per A1 - Ricceri, Fulvio A1 - Melander, Olle A1 - Sacerdote, Carlotta A1 - Gamble, Dale M A1 - Rayaprolu, Sruti A1 - Ross, Owen A A1 - McLachlan, Stela A1 - Vikhireva, Olga A1 - Sluijs, Ivonne A1 - Scott, Robert A A1 - Adamkova, Vera A1 - Flicker, Leon A1 - Bockxmeer, Frank M van A1 - Power, Christine A1 - Marques-Vidal, Pedro A1 - Meade, Tom A1 - Marmot, Michael G A1 - Ferro, Jose M A1 - Paulos-Pinheiro, Sofia A1 - Humphries, Steve E A1 - Talmud, Philippa J A1 - Mateo Leach, Irene A1 - Verweij, Niek A1 - Linneberg, Allan A1 - Skaaby, Tea A1 - Doevendans, Pieter A A1 - Cramer, Maarten J A1 - van der Harst, Pim A1 - Klungel, Olaf H A1 - Dowling, Nicole F A1 - Dominiczak, Anna F A1 - Kumari, Meena A1 - Nicolaides, Andrew N A1 - Weikert, Cornelia A1 - Boeing, Heiner A1 - Ebrahim, Shah A1 - Gaunt, Tom R A1 - Price, Jackie F A1 - Lannfelt, Lars A1 - Peasey, Anne A1 - Kubinova, Ruzena A1 - Pajak, Andrzej A1 - Malyutina, Sofia A1 - Voevoda, Mikhail I A1 - Tamosiunas, Abdonas A1 - Maitland-van der Zee, Anke H A1 - Norman, Paul E A1 - Hankey, Graeme J A1 - Bergmann, Manuela M A1 - Hofman, Albert A1 - Franco, Oscar H A1 - Cooper, Jackie A1 - Palmen, Jutta A1 - Spiering, Wilko A1 - de Jong, Pim A A1 - Kuh, Diana A1 - Hardy, Rebecca A1 - Uitterlinden, André G A1 - Ikram, M Arfan A1 - Ford, Ian A1 - Hyppönen, Elina A1 - Almeida, Osvaldo P A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Hamsten, Anders A1 - Husemoen, Lise Lotte N A1 - Tjønneland, Anne A1 - Tolstrup, Janne S A1 - Rimm, Eric A1 - Beulens, Joline W J A1 - Verschuren, W M Monique A1 - Onland-Moret, N Charlotte A1 - Hofker, Marten H A1 - Wannamethee, S Goya A1 - Whincup, Peter H A1 - Morris, Richard A1 - Vicente, Astrid M A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Jukema, J Wouter A1 - Meschia, James A1 - Cupples, L Adrienne A1 - Sharp, Stephen J A1 - Fornage, Myriam A1 - Kooperberg, Charles A1 - LaCroix, Andrea Z A1 - Dai, James Y A1 - Lanktree, Matthew B A1 - Siscovick, David S A1 - Jorgenson, Eric A1 - Spring, Bonnie A1 - Coresh, Josef A1 - Li, Yun R A1 - Buxbaum, Sarah G A1 - Schreiner, Pamela J A1 - Ellison, R Curtis A1 - Tsai, Michael Y A1 - Patel, Sanjay R A1 - Redline, Susan A1 - Johnson, Andrew D A1 - Hoogeveen, Ron C A1 - Hakonarson, Hakon A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - de Bakker, Paul I W A1 - Kivimaki, Mika A1 - Asselbergs, Folkert W A1 - Sattar, Naveed A1 - Lawlor, Debbie A A1 - Whittaker, John A1 - Davey Smith, George A1 - Mukamal, Kenneth A1 - Psaty, Bruce M A1 - Wilson, James G A1 - Lange, Leslie A A1 - Hamidovic, Ajna A1 - Hingorani, Aroon D A1 - Nordestgaard, Børge G A1 - Bobak, Martin A1 - Leon, David A A1 - Langenberg, Claudia A1 - Palmer, Tom M A1 - Reiner, Alex P A1 - Keating, Brendan J A1 - Dudbridge, Frank A1 - Casas, Juan P KW - Adult KW - Aged KW - Alcohol Dehydrogenase KW - Alcohol Drinking KW - Biomarkers KW - Coronary Disease KW - Female KW - Genetic Markers KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Models, Statistical KW - Polymorphism, Single Nucleotide KW - Stroke AB -

OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease.

DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies.

PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers.

MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption.

RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)).

CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.

VL - 349 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25011450?dopt=Abstract ER - TY - JOUR T1 - FTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals. JF - Hum Mol Genet Y1 - 2014 A1 - Qi, Qibin A1 - Kilpeläinen, Tuomas O A1 - Downer, Mary K A1 - Tanaka, Toshiko A1 - Smith, Caren E A1 - Sluijs, Ivonne A1 - Sonestedt, Emily A1 - Chu, Audrey Y A1 - Renstrom, Frida A1 - Lin, Xiaochen A1 - Ängquist, Lars H A1 - Huang, Jinyan A1 - Liu, Zhonghua A1 - Li, Yanping A1 - Asif Ali, Muhammad A1 - Xu, Min A1 - Ahluwalia, Tarunveer Singh A1 - Boer, Jolanda M A A1 - Chen, Peng A1 - Daimon, Makoto A1 - Eriksson, Johan A1 - Perola, Markus A1 - Friedlander, Yechiel A1 - Gao, Yu-Tang A1 - Heppe, Denise H M A1 - Holloway, John W A1 - Houston, Denise K A1 - Kanoni, Stavroula A1 - Kim, Yu-Mi A1 - Laaksonen, Maarit A A1 - Jääskeläinen, Tiina A1 - Lee, Nanette R A1 - Lehtimäki, Terho A1 - Lemaitre, Rozenn N A1 - Lu, Wei A1 - Luben, Robert N A1 - Manichaikul, Ani A1 - Männistö, Satu A1 - Marques-Vidal, Pedro A1 - Monda, Keri L A1 - Ngwa, Julius S A1 - Perusse, Louis A1 - van Rooij, Frank J A A1 - Xiang, Yong-Bing A1 - Wen, Wanqing A1 - Wojczynski, Mary K A1 - Zhu, Jingwen A1 - Borecki, Ingrid B A1 - Bouchard, Claude A1 - Cai, Qiuyin A1 - Cooper, Cyrus A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Hansen, Torben A1 - Christiansen, Lene A1 - Hofman, Albert A1 - Johansson, Ingegerd A1 - Jørgensen, Torben A1 - Karasawa, Shigeru A1 - Khaw, Kay-Tee A1 - Kim, Mi-Kyung A1 - Kristiansson, Kati A1 - Li, Huaixing A1 - Lin, Xu A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Mikkilä, Vera A1 - Mozaffarian, Dariush A1 - North, Kari A1 - Pedersen, Oluf A1 - Raitakari, Olli A1 - Rissanen, Harri A1 - Tuomilehto, Jaakko A1 - van der Schouw, Yvonne T A1 - Uitterlinden, André G A1 - Zillikens, M Carola A1 - Franco, Oscar H A1 - Shyong Tai, E A1 - Ou Shu, Xiao A1 - Siscovick, David S A1 - Toft, Ulla A1 - Verschuren, W M Monique A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Witteman, Jacqueline C M A1 - Zheng, Wei A1 - Ridker, Paul M A1 - Kang, Jae H A1 - Liang, Liming A1 - Jensen, Majken K A1 - Curhan, Gary C A1 - Pasquale, Louis R A1 - Hunter, David J A1 - Mohlke, Karen L A1 - Uusitupa, Matti A1 - Cupples, L Adrienne A1 - Rankinen, Tuomo A1 - Orho-Melander, Marju A1 - Wang, Tao A1 - Chasman, Daniel I A1 - Franks, Paul W A1 - Sørensen, Thorkild I A A1 - Hu, Frank B A1 - Loos, Ruth J F A1 - Nettleton, Jennifer A A1 - Qi, Lu KW - Adult KW - African Americans KW - Aged KW - Alleles KW - Asian Continental Ancestry Group KW - Body Mass Index KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins AB -

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

VL - 23 IS - 25 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25104851?dopt=Abstract ER - TY - JOUR T1 - Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. JF - Am J Hum Genet Y1 - 2014 A1 - Simino, Jeannette A1 - Shi, Gang A1 - Bis, Joshua C A1 - Chasman, Daniel I A1 - Ehret, Georg B A1 - Gu, Xiangjun A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Sijbrands, Eric A1 - Smith, Albert V A1 - Verwoert, Germaine C A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - Chen, Peng A1 - Cheng, Ching-Yu A1 - Corre, Tanguy A1 - de Boer, Rudolf A A1 - Goel, Anuj A1 - Johnson, Toby A1 - Khor, Chiea-Chuen A1 - Lluís-Ganella, Carla A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Sim, Xueling A1 - Sõber, Siim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Bouchard, Claude A1 - Dehghan, Abbas A1 - Eiriksdottir, Gudny A1 - Elosua, Roberto A1 - Franco, Oscar H A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Hercberg, Serge A1 - Hofman, Albert A1 - James, Alan L A1 - Johnson, Andrew D A1 - Kähönen, Mika A1 - Khaw, Kay-Tee A1 - Kutalik, Zoltán A1 - Larson, Martin G A1 - Launer, Lenore J A1 - Li, Guo A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Navis, Gerjan A1 - Ong, Rick Twee-Hee A1 - Papanicolau, George J A1 - Penninx, Brenda W A1 - Psaty, Bruce M A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scott, Robert A A1 - Siscovick, David S A1 - Stolk, Ronald P A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Klauw, Melanie M A1 - Vasan, Ramachandran S A1 - Vithana, Eranga Nishanthie A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Young, Terri L A1 - Aung, Tin A1 - Bochud, Murielle A1 - Farrall, Martin A1 - Hartman, Catharina A A1 - Laan, Maris A1 - Lakatta, Edward G A1 - Lehtimäki, Terho A1 - Loos, Ruth J F A1 - Lucas, Gavin A1 - Meneton, Pierre A1 - Palmer, Lyle J A1 - Rettig, Rainer A1 - Snieder, Harold A1 - Tai, E Shyong A1 - Teo, Yik-Ying A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Wong, Tien Yin A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Levy, Daniel A1 - Palmas, Walter A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - van Duijn, Cornelia M A1 - Witteman, Jacqueline C M A1 - Chakravarti, Aravinda A1 - Rao, Dabeeru C KW - Adolescent KW - Adult KW - Age Factors KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Humans KW - Middle Aged KW - Young Adult AB -

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

VL - 95 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24954895?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies six new loci associated with forced vital capacity. JF - Nat Genet Y1 - 2014 A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Wain, Louise V A1 - Franceschini, Nora A1 - Koch, Beate A1 - Pottinger, Tess D A1 - Smith, Albert Vernon A1 - Duan, Qing A1 - Oldmeadow, Chris A1 - Lee, Mi Kyeong A1 - Strachan, David P A1 - James, Alan L A1 - Huffman, Jennifer E A1 - Vitart, Veronique A1 - Ramasamy, Adaikalavan A1 - Wareham, Nicholas J A1 - Kaprio, Jaakko A1 - Wang, Xin-Qun A1 - Trochet, Holly A1 - Kähönen, Mika A1 - Flexeder, Claudia A1 - Albrecht, Eva A1 - Lopez, Lorna M A1 - de Jong, Kim A1 - Thyagarajan, Bharat A1 - Alves, Alexessander Couto A1 - Enroth, Stefan A1 - Omenaas, Ernst A1 - Joshi, Peter K A1 - Fall, Tove A1 - Viñuela, Ana A1 - Launer, Lenore J A1 - Loehr, Laura R A1 - Fornage, Myriam A1 - Li, Guo A1 - Wilk, Jemma B A1 - Tang, Wenbo A1 - Manichaikul, Ani A1 - Lahousse, Lies A1 - Harris, Tamara B A1 - North, Kari E A1 - Rudnicka, Alicja R A1 - Hui, Jennie A1 - Gu, Xiangjun A1 - Lumley, Thomas A1 - Wright, Alan F A1 - Hastie, Nicholas D A1 - Campbell, Susan A1 - Kumar, Rajesh A1 - Pin, Isabelle A1 - Scott, Robert A A1 - Pietiläinen, Kirsi H A1 - Surakka, Ida A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Schulz, Holger A1 - Heinrich, Joachim A1 - Davies, Gail A1 - Vonk, Judith M A1 - Wojczynski, Mary A1 - Pouta, Anneli A1 - Johansson, Asa A1 - Wild, Sarah H A1 - Ingelsson, Erik A1 - Rivadeneira, Fernando A1 - Völzke, Henry A1 - Hysi, Pirro G A1 - Eiriksdottir, Gudny A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Gao, Wei A1 - Postma, Dirkje S A1 - White, Wendy B A1 - Rich, Stephen S A1 - Hofman, Albert A1 - Aspelund, Thor A1 - Couper, David A1 - Smith, Lewis J A1 - Psaty, Bruce M A1 - Lohman, Kurt A1 - Burchard, Esteban G A1 - Uitterlinden, André G A1 - Garcia, Melissa A1 - Joubert, Bonnie R A1 - McArdle, Wendy L A1 - Musk, A Bill A1 - Hansel, Nadia A1 - Heckbert, Susan R A1 - Zgaga, Lina A1 - van Meurs, Joyce B J A1 - Navarro, Pau A1 - Rudan, Igor A1 - Oh, Yeon-Mok A1 - Redline, Susan A1 - Jarvis, Deborah L A1 - Zhao, Jing Hua A1 - Rantanen, Taina A1 - O'Connor, George T A1 - Ripatti, Samuli A1 - Scott, Rodney J A1 - Karrasch, Stefan A1 - Grallert, Harald A1 - Gaddis, Nathan C A1 - Starr, John M A1 - Wijmenga, Cisca A1 - Minster, Ryan L A1 - Lederer, David J A1 - Pekkanen, Juha A1 - Gyllensten, Ulf A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Gläser, Sven A1 - Hammond, Christopher J A1 - Burkart, Kristin M A1 - Beilby, John A1 - Kritchevsky, Stephen B A1 - Gudnason, Vilmundur A1 - Hancock, Dana B A1 - Williams, O Dale A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Petrini, Marcy F A1 - Wjst, Matthias A1 - Kim, Woo Jin A1 - Porteous, David J A1 - Scotland, Generation A1 - Smith, Blair H A1 - Viljanen, Anne A1 - Heliövaara, Markku A1 - Attia, John R A1 - Sayers, Ian A1 - Hampel, Regina A1 - Gieger, Christian A1 - Deary, Ian J A1 - Boezen, H Marike A1 - Newman, Anne A1 - Jarvelin, Marjo-Riitta A1 - Wilson, James F A1 - Lind, Lars A1 - Stricker, Bruno H A1 - Teumer, Alexander A1 - Spector, Timothy D A1 - Melén, Erik A1 - Peters, Marjolein J A1 - Lange, Leslie A A1 - Barr, R Graham A1 - Bracke, Ken R A1 - Verhamme, Fien M A1 - Sung, Joohon A1 - Hiemstra, Pieter S A1 - Cassano, Patricia A A1 - Sood, Akshay A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Hall, Ian P A1 - Brusselle, Guy G A1 - Tobin, Martin D A1 - London, Stephanie J KW - Cohort Studies KW - Databases, Genetic KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung Diseases KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Quantitative Trait Loci KW - Respiratory Function Tests KW - Spirometry KW - Vital Capacity AB -

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

VL - 46 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract ER - TY - JOUR T1 - Glycated hemoglobin measurement and prediction of cardiovascular disease. JF - JAMA Y1 - 2014 A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Khan, Hassan A1 - Butterworth, Adam S A1 - Wormser, David A1 - Kaptoge, Stephen A1 - Kondapally Seshasai, Sreenivasa Rao A1 - Thompson, Alex A1 - Sarwar, Nadeem A1 - Willeit, Peter A1 - Ridker, Paul M A1 - Barr, Elizabeth L M A1 - Khaw, Kay-Tee A1 - Psaty, Bruce M A1 - Brenner, Hermann A1 - Balkau, Beverley A1 - Dekker, Jacqueline M A1 - Lawlor, Debbie A A1 - Daimon, Makoto A1 - Willeit, Johann A1 - Njølstad, Inger A1 - Nissinen, Aulikki A1 - Brunner, Eric J A1 - Kuller, Lewis H A1 - Price, Jackie F A1 - Sundström, Johan A1 - Knuiman, Matthew W A1 - Feskens, Edith J M A1 - Verschuren, W M M A1 - Wald, Nicholas A1 - Bakker, Stephan J L A1 - Whincup, Peter H A1 - Ford, Ian A1 - Goldbourt, Uri A1 - Gómez-de-la-Cámara, Agustín A1 - Gallacher, John A1 - Simons, Leon A A1 - Rosengren, Annika A1 - Sutherland, Susan E A1 - Björkelund, Cecilia A1 - Blazer, Dan G A1 - Wassertheil-Smoller, Sylvia A1 - Onat, Altan A1 - Marín Ibañez, Alejandro A1 - Casiglia, Edoardo A1 - Jukema, J Wouter A1 - Simpson, Lara M A1 - Giampaoli, Simona A1 - Nordestgaard, Børge G A1 - Selmer, Randi A1 - Wennberg, Patrik A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Dankner, Rachel A1 - Barrett-Connor, Elizabeth A1 - Kavousi, Maryam A1 - Gudnason, Vilmundur A1 - Evans, Denis A1 - Wallace, Robert B A1 - Cushman, Mary A1 - D'Agostino, Ralph B A1 - Umans, Jason G A1 - Kiyohara, Yutaka A1 - Nakagawa, Hidaeki A1 - Sato, Shinichi A1 - Gillum, Richard F A1 - Folsom, Aaron R A1 - van der Schouw, Yvonne T A1 - Moons, Karel G A1 - Griffin, Simon J A1 - Sattar, Naveed A1 - Wareham, Nicholas J A1 - Selvin, Elizabeth A1 - Thompson, Simon G A1 - Danesh, John KW - Aged KW - C-Reactive Protein KW - Cholesterol, HDL KW - Coronary Disease KW - Diabetes Mellitus KW - Female KW - Glycated Hemoglobin A KW - Humans KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Assessment KW - Stroke AB -

IMPORTANCE: The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.

OBJECTIVE: To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.

DESIGN, SETTING, AND PARTICIPANTS: Analysis of individual-participant data available from 73 prospective studies involving 294,998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.

MAIN OUTCOMES AND MEASURES: Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5% to <7.5%), and high (≥ 7.5%) risk.

RESULTS: During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20,840 incident fatal and nonfatal CVD outcomes (13,237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (-0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.

CONCLUSIONS AND RELEVANCE: In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.

VL - 311 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24668104?dopt=Abstract ER - TY - JOUR T1 - Association of Cardiometabolic Multimorbidity With Mortality. JF - JAMA Y1 - 2015 A1 - Di Angelantonio, Emanuele A1 - Kaptoge, Stephen A1 - Wormser, David A1 - Willeit, Peter A1 - Butterworth, Adam S A1 - Bansal, Narinder A1 - O'Keeffe, Linda M A1 - Gao, Pei A1 - Wood, Angela M A1 - Burgess, Stephen A1 - Freitag, Daniel F A1 - Pennells, Lisa A1 - Peters, Sanne A A1 - Hart, Carole L A1 - Håheim, Lise Lund A1 - Gillum, Richard F A1 - Nordestgaard, Børge G A1 - Psaty, Bruce M A1 - Yeap, Bu B A1 - Knuiman, Matthew W A1 - Nietert, Paul J A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Kuller, Lewis H A1 - Simons, Leon A A1 - van der Schouw, Yvonne T A1 - Barrett-Connor, Elizabeth A1 - Selmer, Randi A1 - Crespo, Carlos J A1 - Rodriguez, Beatriz A1 - Verschuren, W M Monique A1 - Salomaa, Veikko A1 - Svärdsudd, Kurt A1 - van der Harst, Pim A1 - Björkelund, Cecilia A1 - Wilhelmsen, Lars A1 - Wallace, Robert B A1 - Brenner, Hermann A1 - Amouyel, Philippe A1 - Barr, Elizabeth L M A1 - Iso, Hiroyasu A1 - Onat, Altan A1 - Trevisan, Maurizio A1 - D'Agostino, Ralph B A1 - Cooper, Cyrus A1 - Kavousi, Maryam A1 - Welin, Lennart A1 - Roussel, Ronan A1 - Hu, Frank B A1 - Sato, Shinichi A1 - Davidson, Karina W A1 - Howard, Barbara V A1 - Leening, Maarten J G A1 - Leening, Maarten A1 - Rosengren, Annika A1 - Dörr, Marcus A1 - Deeg, Dorly J H A1 - Kiechl, Stefan A1 - Stehouwer, Coen D A A1 - Nissinen, Aulikki A1 - Giampaoli, Simona A1 - Donfrancesco, Chiara A1 - Kromhout, Daan A1 - Price, Jackie F A1 - Peters, Annette A1 - Meade, Tom W A1 - Casiglia, Edoardo A1 - Lawlor, Debbie A A1 - Gallacher, John A1 - Nagel, Dorothea A1 - Franco, Oscar H A1 - Assmann, Gerd A1 - Dagenais, Gilles R A1 - Jukema, J Wouter A1 - Sundström, Johan A1 - Woodward, Mark A1 - Brunner, Eric J A1 - Khaw, Kay-Tee A1 - Wareham, Nicholas J A1 - Whitsel, Eric A A1 - Njølstad, Inger A1 - Hedblad, Bo A1 - Wassertheil-Smoller, Sylvia A1 - Engström, Gunnar A1 - Rosamond, Wayne D A1 - Selvin, Elizabeth A1 - Sattar, Naveed A1 - Thompson, Simon G A1 - Danesh, John KW - Adult KW - Aged KW - Comorbidity KW - Diabetes Mellitus KW - Female KW - Humans KW - Life Expectancy KW - Male KW - Middle Aged KW - Mortality KW - Myocardial Infarction KW - Risk Factors KW - Stroke AB -

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing.

OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.

DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates.

EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).

MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy.

RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.

CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

VL - 314 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26151266?dopt=Abstract ER - TY - JOUR T1 - Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. JF - Nat Commun Y1 - 2015 A1 - Wessel, Jennifer A1 - Chu, Audrey Y A1 - Willems, Sara M A1 - Wang, Shuai A1 - Yaghootkar, Hanieh A1 - Brody, Jennifer A A1 - Dauriz, Marco A1 - Hivert, Marie-France A1 - Raghavan, Sridharan A1 - Lipovich, Leonard A1 - Hidalgo, Bertha A1 - Fox, Keolu A1 - Huffman, Jennifer E A1 - An, Ping A1 - Lu, Yingchang A1 - Rasmussen-Torvik, Laura J A1 - Grarup, Niels A1 - Ehm, Margaret G A1 - Li, Li A1 - Baldridge, Abigail S A1 - Stančáková, Alena A1 - Abrol, Ravinder A1 - Besse, Céline A1 - Boland, Anne A1 - Bork-Jensen, Jette A1 - Fornage, Myriam A1 - Freitag, Daniel F A1 - Garcia, Melissa E A1 - Guo, Xiuqing A1 - Hara, Kazuo A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Lange, Leslie A A1 - Layton, Jill C A1 - Li, Man A1 - Hua Zhao, Jing A1 - Meidtner, Karina A1 - Morrison, Alanna C A1 - Nalls, Mike A A1 - Peters, Marjolein J A1 - Sabater-Lleal, Maria A1 - Schurmann, Claudia A1 - Silveira, Angela A1 - Smith, Albert V A1 - Southam, Lorraine A1 - Stoiber, Marcus H A1 - Strawbridge, Rona J A1 - Taylor, Kent D A1 - Varga, Tibor V A1 - Allin, Kristine H A1 - Amin, Najaf A1 - Aponte, Jennifer L A1 - Aung, Tin A1 - Barbieri, Caterina A1 - Bihlmeyer, Nathan A A1 - Boehnke, Michael A1 - Bombieri, Cristina A1 - Bowden, Donald W A1 - Burns, Sean M A1 - Chen, Yuning A1 - Chen, Yii-DerI A1 - Cheng, Ching-Yu A1 - Correa, Adolfo A1 - Czajkowski, Jacek A1 - Dehghan, Abbas A1 - Ehret, Georg B A1 - Eiriksdottir, Gudny A1 - Escher, Stefan A A1 - Farmaki, Aliki-Eleni A1 - Frånberg, Mattias A1 - Gambaro, Giovanni A1 - Giulianini, Franco A1 - Goddard, William A A1 - Goel, Anuj A1 - Gottesman, Omri A1 - Grove, Megan L A1 - Gustafsson, Stefan A1 - Hai, Yang A1 - Hallmans, Göran A1 - Heo, Jiyoung A1 - Hoffmann, Per A1 - Ikram, Mohammad K A1 - Jensen, Richard A A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Karaleftheri, Maria A1 - Khor, Chiea C A1 - Kirkpatrick, Andrea A1 - Kraja, Aldi T A1 - Kuusisto, Johanna A1 - Lange, Ethan M A1 - Lee, I T A1 - Lee, Wen-Jane A1 - Leong, Aaron A1 - Liao, Jiemin A1 - Liu, Chunyu A1 - Liu, Yongmei A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Malerba, Giovanni A1 - Mamakou, Vasiliki A1 - Marouli, Eirini A1 - Maruthur, Nisa M A1 - Matchan, Angela A1 - McKean-Cowdin, Roberta A1 - McLeod, Olga A1 - Metcalf, Ginger A A1 - Mohlke, Karen L A1 - Muzny, Donna M A1 - Ntalla, Ioanna A1 - Palmer, Nicholette D A1 - Pasko, Dorota A1 - Peter, Andreas A1 - Rayner, Nigel W A1 - Renstrom, Frida A1 - Rice, Ken A1 - Sala, Cinzia F A1 - Sennblad, Bengt A1 - Serafetinidis, Ioannis A1 - Smith, Jennifer A A1 - Soranzo, Nicole A1 - Speliotes, Elizabeth K A1 - Stahl, Eli A A1 - Stirrups, Kathleen A1 - Tentolouris, Nikos A1 - Thanopoulou, Anastasia A1 - Torres, Mina A1 - Traglia, Michela A1 - Tsafantakis, Emmanouil A1 - Javad, Sundas A1 - Yanek, Lisa R A1 - Zengini, Eleni A1 - Becker, Diane M A1 - Bis, Joshua C A1 - Brown, James B A1 - Cupples, L Adrienne A1 - Hansen, Torben A1 - Ingelsson, Erik A1 - Karter, Andrew J A1 - Lorenzo, Carlos A1 - Mathias, Rasika A A1 - Norris, Jill M A1 - Peloso, Gina M A1 - Sheu, Wayne H-H A1 - Toniolo, Daniela A1 - Vaidya, Dhananjay A1 - Varma, Rohit A1 - Wagenknecht, Lynne E A1 - Boeing, Heiner A1 - Bottinger, Erwin P A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Ferrannini, Ele A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Gibbs, Richard A A1 - Gudnason, Vilmundur A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Jansson, Jan-Håkan A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Oostra, Ben A A1 - O'Donnell, Christopher J A1 - O'Rahilly, Stephen A1 - Padmanabhan, Sandosh A1 - Pankow, James S A1 - Polasek, Ozren A1 - Province, Michael A A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rudan, Igor A1 - Schulze, Matthias B A1 - Smith, Blair H A1 - Uitterlinden, André G A1 - Walker, Mark A1 - Watkins, Hugh A1 - Wong, Tien Y A1 - Zeggini, Eleftheria A1 - Laakso, Markku A1 - Borecki, Ingrid B A1 - Chasman, Daniel I A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Tai, E Shyong A1 - van Duijn, Cornelia M A1 - Wareham, Nicholas J A1 - Waterworth, Dawn M A1 - Boerwinkle, Eric A1 - Kao, W H Linda A1 - Florez, Jose C A1 - Loos, Ruth J F A1 - Wilson, James G A1 - Frayling, Timothy M A1 - Siscovick, David S A1 - Dupuis, Josée A1 - Rotter, Jerome I A1 - Meigs, James B A1 - Scott, Robert A A1 - Goodarzi, Mark O KW - African Continental Ancestry Group KW - Blood Glucose KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Exome KW - Fasting KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Glucagon-Like Peptide-1 Receptor KW - Glucose-6-Phosphatase KW - Humans KW - Insulin KW - Mutation Rate KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide AB -

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25631608?dopt=Abstract ER - TY - JOUR T1 - DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases. JF - Genome Biol Y1 - 2016 A1 - Ligthart, Symen A1 - Marzi, Carola A1 - Aslibekyan, Stella A1 - Mendelson, Michael M A1 - Conneely, Karen N A1 - Tanaka, Toshiko A1 - Colicino, Elena A1 - Waite, Lindsay L A1 - Joehanes, Roby A1 - Guan, Weihua A1 - Brody, Jennifer A A1 - Elks, Cathy A1 - Marioni, Riccardo A1 - Jhun, Min A A1 - Agha, Golareh A1 - Bressler, Jan A1 - Ward-Caviness, Cavin K A1 - Chen, Brian H A1 - Huan, Tianxiao A1 - Bakulski, Kelly A1 - Salfati, Elias L A1 - Fiorito, Giovanni A1 - Wahl, Simone A1 - Schramm, Katharina A1 - Sha, Jin A1 - Hernandez, Dena G A1 - Just, Allan C A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Pilling, Luke C A1 - Pankow, James S A1 - Tsao, Phil S A1 - Liu, Chunyu A1 - Zhao, Wei A1 - Guarrera, Simonetta A1 - Michopoulos, Vasiliki J A1 - Smith, Alicia K A1 - Peters, Marjolein J A1 - Melzer, David A1 - Vokonas, Pantel A1 - Fornage, Myriam A1 - Prokisch, Holger A1 - Bis, Joshua C A1 - Chu, Audrey Y A1 - Herder, Christian A1 - Grallert, Harald A1 - Yao, Chen A1 - Shah, Sonia A1 - McRae, Allan F A1 - Lin, Honghuang A1 - Horvath, Steve A1 - Fallin, Daniele A1 - Hofman, Albert A1 - Wareham, Nicholas J A1 - Wiggins, Kerri L A1 - Feinberg, Andrew P A1 - Starr, John M A1 - Visscher, Peter M A1 - Murabito, Joanne M A1 - Kardia, Sharon L R A1 - Absher, Devin M A1 - Binder, Elisabeth B A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Peters, Annette A1 - Waldenberger, Melanie A1 - Matullo, Giuseppe A1 - Schwartz, Joel D A1 - Demerath, Ellen W A1 - Uitterlinden, André G A1 - van Meurs, Joyce B J A1 - Franco, Oscar H A1 - Chen, Yii-Der Ida A1 - Levy, Daniel A1 - Turner, Stephen T A1 - Deary, Ian J A1 - Ressler, Kerry J A1 - Dupuis, Josée A1 - Ferrucci, Luigi A1 - Ong, Ken K A1 - Assimes, Themistocles L A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Arnett, Donna K A1 - Baccarelli, Andrea A A1 - Benjamin, Emelia J A1 - Dehghan, Abbas AB -

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.

RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.

CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

VL - 17 IS - 1 ER - TY - JOUR T1 - Epigenetic Signatures of Cigarette Smoking. JF - Circ Cardiovasc Genet Y1 - 2016 A1 - Joehanes, Roby A1 - Just, Allan C A1 - Marioni, Riccardo E A1 - Pilling, Luke C A1 - Reynolds, Lindsay M A1 - Mandaviya, Pooja R A1 - Guan, Weihua A1 - Xu, Tao A1 - Elks, Cathy E A1 - Aslibekyan, Stella A1 - Moreno-Macias, Hortensia A1 - Smith, Jennifer A A1 - Brody, Jennifer A A1 - Dhingra, Radhika A1 - Yousefi, Paul A1 - Pankow, James S A1 - Kunze, Sonja A1 - Shah, Sonia H A1 - McRae, Allan F A1 - Lohman, Kurt A1 - Sha, Jin A1 - Absher, Devin M A1 - Ferrucci, Luigi A1 - Zhao, Wei A1 - Demerath, Ellen W A1 - Bressler, Jan A1 - Grove, Megan L A1 - Huan, Tianxiao A1 - Liu, Chunyu A1 - Mendelson, Michael M A1 - Yao, Chen A1 - Kiel, Douglas P A1 - Peters, Annette A1 - Wang-Sattler, Rui A1 - Visscher, Peter M A1 - Wray, Naomi R A1 - Starr, John M A1 - Ding, Jingzhong A1 - Rodriguez, Carlos J A1 - Wareham, Nicholas J A1 - Irvin, Marguerite R A1 - Zhi, Degui A1 - Barrdahl, Myrto A1 - Vineis, Paolo A1 - Ambatipudi, Srikant A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Schwartz, Joel A1 - Colicino, Elena A1 - Hou, Lifang A1 - Vokonas, Pantel S A1 - Hernandez, Dena G A1 - Singleton, Andrew B A1 - Bandinelli, Stefania A1 - Turner, Stephen T A1 - Ware, Erin B A1 - Smith, Alicia K A1 - Klengel, Torsten A1 - Binder, Elisabeth B A1 - Psaty, Bruce M A1 - Taylor, Kent D A1 - Gharib, Sina A A1 - Swenson, Brenton R A1 - Liang, Liming A1 - DeMeo, Dawn L A1 - O'Connor, George T A1 - Herceg, Zdenko A1 - Ressler, Kerry J A1 - Conneely, Karen N A1 - Sotoodehnia, Nona A1 - Kardia, Sharon L R A1 - Melzer, David A1 - Baccarelli, Andrea A A1 - van Meurs, Joyce B J A1 - Romieu, Isabelle A1 - Arnett, Donna K A1 - Ong, Ken K A1 - Liu, Yongmei A1 - Waldenberger, Melanie A1 - Deary, Ian J A1 - Fornage, Myriam A1 - Levy, Daniel A1 - London, Stephanie J AB -

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders.

METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10(-7) (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10(-7) (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs.

CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

VL - 9 IS - 5 ER - TY - JOUR T1 - General Framework for Meta-Analysis of Haplotype Association Tests. JF - Genet Epidemiol Y1 - 2016 A1 - Wang, Shuai A1 - Zhao, Jing Hua A1 - An, Ping A1 - Guo, Xiuqing A1 - Jensen, Richard A A1 - Marten, Jonathan A1 - Huffman, Jennifer E A1 - Meidtner, Karina A1 - Boeing, Heiner A1 - Campbell, Archie A1 - Rice, Kenneth M A1 - Scott, Robert A A1 - Yao, Jie A1 - Schulze, Matthias B A1 - Wareham, Nicholas J A1 - Borecki, Ingrid B A1 - Province, Michael A A1 - Rotter, Jerome I A1 - Hayward, Caroline A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Dupuis, Josée AB -

For complex traits, most associated single nucleotide variants (SNV) discovered to date have a small effect, and detection of association is only possible with large sample sizes. Because of patient confidentiality concerns, it is often not possible to pool genetic data from multiple cohorts, and meta-analysis has emerged as the method of choice to combine results from multiple studies. Many meta-analysis methods are available for single SNV analyses. As new approaches allow the capture of low frequency and rare genetic variation, it is of interest to jointly consider multiple variants to improve power. However, for the analysis of haplotypes formed by multiple SNVs, meta-analysis remains a challenge, because different haplotypes may be observed across studies. We propose a two-stage meta-analysis approach to combine haplotype analysis results. In the first stage, each cohort estimate haplotype effect sizes in a regression framework, accounting for relatedness among observations if appropriate. For the second stage, we use a multivariate generalized least square meta-analysis approach to combine haplotype effect estimates from multiple cohorts. Haplotype-specific association tests and a global test of independence between haplotypes and traits are obtained within our framework. We demonstrate through simulation studies that we control the type-I error rate, and our approach is more powerful than inverse variance weighted meta-analysis of single SNV analysis when haplotype effects are present. We replicate a published haplotype association between fasting glucose-associated locus (G6PC2) and fasting glucose in seven studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and we provide more precise haplotype effect estimates.

VL - 40 IS - 3 ER - TY - JOUR T1 - Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci. JF - Diabetes Y1 - 2016 A1 - Walford, Geoffrey A A1 - Gustafsson, Stefan A1 - Rybin, Denis A1 - Stančáková, Alena A1 - Chen, Han A1 - Liu, Ching-Ti A1 - Hong, Jaeyoung A1 - Jensen, Richard A A1 - Rice, Ken A1 - Morris, Andrew P A1 - Mägi, Reedik A1 - Tönjes, Anke A1 - Prokopenko, Inga A1 - Kleber, Marcus E A1 - Delgado, Graciela A1 - Silbernagel, Günther A1 - Jackson, Anne U A1 - Appel, Emil V A1 - Grarup, Niels A1 - Lewis, Joshua P A1 - Montasser, May E A1 - Landenvall, Claes A1 - Staiger, Harald A1 - Luan, Jian'an A1 - Frayling, Timothy M A1 - Weedon, Michael N A1 - Xie, Weijia A1 - Morcillo, Sonsoles A1 - Martínez-Larrad, María Teresa A1 - Biggs, Mary L A1 - Chen, Yii-Der Ida A1 - Corbaton-Anchuelo, Arturo A1 - Færch, Kristine A1 - Gómez-Zumaquero, Juan Miguel A1 - Goodarzi, Mark O A1 - Kizer, Jorge R A1 - Koistinen, Heikki A A1 - Leong, Aaron A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Machicao, Fausto A1 - Manning, Alisa K A1 - Martín-Núñez, Gracia María A1 - Rojo-Martínez, Gemma A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Zmuda, Joseph M A1 - Zhang, Zhongyang A1 - Serrano-Ríos, Manuel A1 - Smith, Ulf A1 - Soriguer, Federico A1 - Hansen, Torben A1 - Jørgensen, Torben J A1 - Linnenberg, Allan A1 - Pedersen, Oluf A1 - Walker, Mark A1 - Langenberg, Claudia A1 - Scott, Robert A A1 - Wareham, Nicholas J A1 - Fritsche, Andreas A1 - Häring, Hans-Ulrich A1 - Stefan, Norbert A1 - Groop, Leif A1 - O'Connell, Jeff R A1 - Boehnke, Michael A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Mohlke, Karen L A1 - Tuomilehto, Jaakko A1 - März, Winfried A1 - Kovacs, Peter A1 - Stumvoll, Michael A1 - Psaty, Bruce M A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Meigs, James B A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Florez, Jose C AB -

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

VL - 65 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27416945?dopt=Abstract ER - TY - JOUR T1 - KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference. JF - Proc Natl Acad Sci U S A Y1 - 2016 A1 - Schumann, Gunter A1 - Liu, Chunyu A1 - O'Reilly, Paul A1 - Gao, He A1 - Song, Parkyong A1 - Xu, Bing A1 - Ruggeri, Barbara A1 - Amin, Najaf A1 - Jia, Tianye A1 - Preis, Sarah A1 - Segura Lepe, Marcelo A1 - Akira, Shizuo A1 - Barbieri, Caterina A1 - Baumeister, Sebastian A1 - Cauchi, Stephane A1 - Clarke, Toni-Kim A1 - Enroth, Stefan A1 - Fischer, Krista A1 - Hällfors, Jenni A1 - Harris, Sarah E A1 - Hieber, Saskia A1 - Hofer, Edith A1 - Hottenga, Jouke-Jan A1 - Johansson, Asa A1 - Joshi, Peter K A1 - Kaartinen, Niina A1 - Laitinen, Jaana A1 - Lemaitre, Rozenn A1 - Loukola, Anu A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Mangino, Massimo A1 - Manichaikul, Ani A1 - Mbarek, Hamdi A1 - Milaneschi, Yuri A1 - Moayyeri, Alireza A1 - Mukamal, Kenneth A1 - Nelson, Christopher A1 - Nettleton, Jennifer A1 - Partinen, Eemil A1 - Rawal, Rajesh A1 - Robino, Antonietta A1 - Rose, Lynda A1 - Sala, Cinzia A1 - Satoh, Takashi A1 - Schmidt, Reinhold A1 - Schraut, Katharina A1 - Scott, Robert A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Teumer, Alexander A1 - Trompet, Stella A1 - Uitterlinden, André G A1 - Venturini, Cristina A1 - Vergnaud, Anne-Claire A1 - Verweij, Niek A1 - Vitart, Veronique A1 - Vuckovic, Dragana A1 - Wedenoja, Juho A1 - Yengo, Loic A1 - Yu, Bing A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Boomsma, Dorret I A1 - Chambers, John A1 - Chasman, Daniel I A1 - Daniela, Toniolo A1 - de Geus, Eco A1 - Deary, Ian A1 - Eriksson, Johan G A1 - Esko, Tõnu A1 - Eulenburg, Volker A1 - Franco, Oscar H A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Grabe, Hans J A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Harris, Tamara B A1 - Hartikainen, Anna-Liisa A1 - Heath, Andrew C A1 - Hocking, Lynne A1 - Hofman, Albert A1 - Huth, Cornelia A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Kaprio, Jaakko A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Liu, Yongmei A1 - Madden, Pamela A F A1 - Martin, Nicholas A1 - Morrison, Alanna A1 - Penninx, Brenda A1 - Pirastu, Nicola A1 - Psaty, Bruce A1 - Raitakari, Olli A1 - Ridker, Paul A1 - Rose, Richard A1 - Rotter, Jerome I A1 - Samani, Nilesh J A1 - Schmidt, Helena A1 - Spector, Tim D A1 - Stott, David A1 - Strachan, David A1 - Tzoulaki, Ioanna A1 - van der Harst, Pim A1 - van Duijn, Cornelia M A1 - Marques-Vidal, Pedro A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wilson, James A1 - Wolffenbuttel, Bruce A1 - Bakalkin, Georgy A1 - Evangelou, Evangelos A1 - Liu, Yun A1 - Rice, Kenneth M A1 - Desrivières, Sylvane A1 - Kliewer, Steven A A1 - Mangelsdorf, David J A1 - Müller, Christian P A1 - Levy, Daniel A1 - Elliott, Paul AB -

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10(-12)). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

VL - 113 IS - 50 ER - TY - JOUR T1 - A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape. JF - Nat Commun Y1 - 2016 A1 - Ried, Janina S A1 - Jeff M, Janina A1 - Chu, Audrey Y A1 - Bragg-Gresham, Jennifer L A1 - van Dongen, Jenny A1 - Huffman, Jennifer E A1 - Ahluwalia, Tarunveer S A1 - Cadby, Gemma A1 - Eklund, Niina A1 - Eriksson, Joel A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Goel, Anuj A1 - Gorski, Mathias A1 - Hayward, Caroline A1 - Heard-Costa, Nancy L A1 - Jackson, Anne U A1 - Jokinen, Eero A1 - Kanoni, Stavroula A1 - Kristiansson, Kati A1 - Kutalik, Zoltán A1 - Lahti, Jari A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Mangino, Massimo A1 - Medina-Gómez, Carolina A1 - Monda, Keri L A1 - Nolte, Ilja M A1 - Perusse, Louis A1 - Prokopenko, Inga A1 - Qi, Lu A1 - Rose, Lynda M A1 - Salvi, Erika A1 - Smith, Megan T A1 - Snieder, Harold A1 - Stančáková, Alena A1 - Ju Sung, Yun A1 - Tachmazidou, Ioanna A1 - Teumer, Alexander A1 - Thorleifsson, Gudmar A1 - van der Harst, Pim A1 - Walker, Ryan W A1 - Wang, Sophie R A1 - Wild, Sarah H A1 - Willems, Sara M A1 - Wong, Andrew A1 - Zhang, Weihua A1 - Albrecht, Eva A1 - Couto Alves, Alexessander A1 - Bakker, Stephan J L A1 - Barlassina, Cristina A1 - Bartz, Traci M A1 - Beilby, John A1 - Bellis, Claire A1 - Bergman, Richard N A1 - Bergmann, Sven A1 - Blangero, John A1 - Blüher, Matthias A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Bornstein, Stefan R A1 - Bruinenberg, Marcel A1 - Campbell, Harry A1 - Chen, Yii-Der Ida A1 - Chiang, Charleston W K A1 - Chines, Peter S A1 - Collins, Francis S A1 - Cucca, Fracensco A1 - Cupples, L Adrienne A1 - D'Avila, Francesca A1 - de Geus, Eco J C A1 - Dedoussis, George A1 - Dimitriou, Maria A1 - Döring, Angela A1 - Eriksson, Johan G A1 - Farmaki, Aliki-Eleni A1 - Farrall, Martin A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Forouhi, Nita G A1 - Friedrich, Nele A1 - Gjesing, Anette Prior A1 - Glorioso, Nicola A1 - Graff, Mariaelisa A1 - Grallert, Harald A1 - Grarup, Niels A1 - Gräßler, Jürgen A1 - Grewal, Jagvir A1 - Hamsten, Anders A1 - Harder, Marie Neergaard A1 - Hartman, Catharina A A1 - Hassinen, Maija A1 - Hastie, Nicholas A1 - Hattersley, Andrew Tym A1 - Havulinna, Aki S A1 - Heliövaara, Markku A1 - Hillege, Hans A1 - Hofman, Albert A1 - Holmen, Oddgeir A1 - Homuth, Georg A1 - Hottenga, Jouke-Jan A1 - Hui, Jennie A1 - Husemoen, Lise Lotte A1 - Hysi, Pirro G A1 - Isaacs, Aaron A1 - Ittermann, Till A1 - Jalilzadeh, Shapour A1 - James, Alan L A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jula, Antti A1 - Marie Justesen, Johanne A1 - Justice, Anne E A1 - Kähönen, Mika A1 - Karaleftheri, Maria A1 - Tee Khaw, Kay A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Kinnunen, Leena A1 - Knekt, Paul B A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooner, Ishminder K A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyriakou, Theodosios A1 - Laitinen, Tomi A1 - Langenberg, Claudia A1 - Lewin, Alexandra M A1 - Lichtner, Peter A1 - Lindgren, Cecilia M A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Lorbeer, Roberto A1 - Lorentzon, Mattias A1 - Luben, Robert A1 - Lyssenko, Valeriya A1 - Männistö, Satu A1 - Manunta, Paolo A1 - Leach, Irene Mateo A1 - McArdle, Wendy L A1 - McKnight, Barbara A1 - Mohlke, Karen L A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Mills, Rebecca A1 - Montasser, May E A1 - Morris, Andrew P A1 - Müller, Gabriele A1 - Musk, Arthur W A1 - Narisu, Narisu A1 - Ong, Ken K A1 - Oostra, Ben A A1 - Osmond, Clive A1 - Palotie, Aarno A1 - Pankow, James S A1 - Paternoster, Lavinia A1 - Penninx, Brenda W A1 - Pichler, Irene A1 - Pilia, Maria G A1 - Polasek, Ozren A1 - Pramstaller, Peter P A1 - Raitakari, Olli T A1 - Rankinen, Tuomo A1 - Rao, D C A1 - Rayner, Nigel W A1 - Ribel-Madsen, Rasmus A1 - Rice, Treva K A1 - Richards, Marcus A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Ryan, Kathy A A1 - Sanna, Serena A1 - Sarzynski, Mark A A1 - Scholtens, Salome A1 - Scott, Robert A A1 - Sebert, Sylvain A1 - Southam, Lorraine A1 - Sparsø, Thomas Hempel A1 - Steinthorsdottir, Valgerdur A1 - Stirrups, Kathleen A1 - Stolk, Ronald P A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Swertz, Morris A A1 - Swift, Amy J A1 - Tönjes, Anke A1 - Tsafantakis, Emmanouil A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Vandenput, Liesbeth A1 - Vartiainen, Erkki A1 - Venturini, Cristina A1 - Verweij, Niek A1 - Viikari, Jorma S A1 - Vitart, Veronique A1 - Vohl, Marie-Claude A1 - Vonk, Judith M A1 - Waeber, Gérard A1 - Widen, Elisabeth A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Winkler, Thomas W A1 - Wright, Alan F A1 - Yerges-Armstrong, Laura M A1 - Hua Zhao, Jing A1 - Zillikens, M Carola A1 - Boomsma, Dorret I A1 - Bouchard, Claude A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Cusi, Daniele A1 - Gansevoort, Ron T A1 - Gieger, Christian A1 - Hansen, Torben A1 - Hicks, Andrew A A1 - Hu, Frank A1 - Hveem, Kristian A1 - Jarvelin, Marjo-Riitta A1 - Kajantie, Eero A1 - Kooner, Jaspal S A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Metspalu, Andres A1 - Njølstad, Inger A1 - Ohlsson, Claes A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Pedersen, Oluf A1 - Perola, Markus A1 - Peters, Annette A1 - Psaty, Bruce M A1 - Puolijoki, Hannu A1 - Rauramaa, Rainer A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Schwarz, Peter E H A1 - Shudiner, Alan R A1 - Smit, Jan H A1 - Sørensen, Thorkild I A A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Tremblay, Angelo A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - Uusitupa, Matti A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Wilson, James F A1 - Zeggini, Eleftheria A1 - Abecasis, Goncalo R A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Deloukas, Panos A1 - van Duijn, Cornelia M A1 - Fox, Caroline A1 - Groop, Leif C A1 - Heid, Iris M A1 - Hunter, David J A1 - Kaplan, Robert C A1 - McCarthy, Mark I A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Schlessinger, David A1 - Thorsteinsdottir, Unnur A1 - Strachan, David P A1 - Frayling, Timothy A1 - Hirschhorn, Joel N A1 - Müller-Nurasyid, Martina A1 - Loos, Ruth J F KW - Anthropometry KW - Body Size KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Models, Genetic KW - Principal Component Analysis AB -

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

VL - 7 ER - TY - JOUR T1 - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. JF - PLoS Med Y1 - 2017 A1 - Wheeler, Eleanor A1 - Leong, Aaron A1 - Liu, Ching-Ti A1 - Hivert, Marie-France A1 - Strawbridge, Rona J A1 - Podmore, Clara A1 - Li, Man A1 - Yao, Jie A1 - Sim, Xueling A1 - Hong, Jaeyoung A1 - Chu, Audrey Y A1 - Zhang, Weihua A1 - Wang, Xu A1 - Chen, Peng A1 - Maruthur, Nisa M A1 - Porneala, Bianca C A1 - Sharp, Stephen J A1 - Jia, Yucheng A1 - Kabagambe, Edmond K A1 - Chang, Li-Ching A1 - Chen, Wei-Min A1 - Elks, Cathy E A1 - Evans, Daniel S A1 - Fan, Qiao A1 - Giulianini, Franco A1 - Go, Min Jin A1 - Hottenga, Jouke-Jan A1 - Hu, Yao A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kim, Young Jin A1 - Kleber, Marcus E A1 - Ladenvall, Claes A1 - Lecoeur, Cécile A1 - Lim, Sing-Hui A1 - Lu, Yingchang A1 - Mahajan, Anubha A1 - Marzi, Carola A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nolte, Ilja M A1 - Rose, Lynda M A1 - Rybin, Denis V A1 - Sanna, Serena A1 - Shi, Yuan A1 - Stram, Daniel O A1 - Takeuchi, Fumihiko A1 - Tan, Shu Pei A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Wong, Andrew A1 - Yengo, Loic A1 - Zhao, Wanting A1 - Goel, Anuj A1 - Martinez Larrad, Maria Teresa A1 - Radke, Dörte A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - van Iperen, Erik P A A1 - Abecasis, Goncalo A1 - Afaq, Saima A1 - Alizadeh, Behrooz Z A1 - Bertoni, Alain G A1 - Bonnefond, Amélie A1 - Böttcher, Yvonne A1 - Bottinger, Erwin P A1 - Campbell, Harry A1 - Carlson, Olga D A1 - Chen, Chien-Hsiun A1 - Cho, Yoon Shin A1 - Garvey, W Timothy A1 - Gieger, Christian A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Hamsten, Anders A1 - Hartman, Catharina A A1 - Herder, Christian A1 - Hsiung, Chao Agnes A1 - Huang, Jie A1 - Igase, Michiya A1 - Isono, Masato A1 - Katsuya, Tomohiro A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kohara, Katsuhiko A1 - Kovacs, Peter A1 - Lee, Juyoung A1 - Lee, Wen-Jane A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Liu, Jianjun A1 - Lobbens, Stephane A1 - Luan, Jian'an A1 - Lyssenko, Valeriya A1 - Meitinger, Thomas A1 - Miki, Tetsuro A1 - Miljkovic, Iva A1 - Moon, Sanghoon A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Pankow, James S A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Ramos, Paula S A1 - Rasmussen-Torvik, Laura A1 - Rathmann, Wolfgang A1 - Rich, Stephen S A1 - Robertson, Neil R A1 - Roden, Michael A1 - Roussel, Ronan A1 - Rudan, Igor A1 - Scott, Robert A A1 - Scott, William R A1 - Sennblad, Bengt A1 - Siscovick, David S A1 - Strauch, Konstantin A1 - Sun, Liang A1 - Swertz, Morris A1 - Tajuddin, Salman M A1 - Taylor, Kent D A1 - Teo, Yik-Ying A1 - Tham, Yih Chung A1 - Tönjes, Anke A1 - Wareham, Nicholas J A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Hingorani, Aroon D A1 - Egan, Josephine A1 - Ferrucci, Luigi A1 - Hovingh, G Kees A1 - Jula, Antti A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Njølstad, Inger A1 - Palmer, Colin N A A1 - Serrano Ríos, Manuel A1 - Stumvoll, Michael A1 - Watkins, Hugh A1 - Aung, Tin A1 - Blüher, Matthias A1 - Boehnke, Michael A1 - Boomsma, Dorret I A1 - Bornstein, Stefan R A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chen, Yduan-Tsong A1 - Cheng, Ching-Yu A1 - Cucca, Francesco A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Evans, Michele K A1 - Fornage, Myriam A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Groop, Leif A1 - Gross, Myron D A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heng, Chew-Kiat A1 - Ingelsson, Erik A1 - Kato, Norihiro A1 - Kim, Bong-Jo A1 - Koh, Woon-Puay A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lin, Xu A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - März, Winfried A1 - McCarthy, Mark I A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Pedersen, Nancy L A1 - Pereira, Mark A A1 - Peters, Annette A1 - Ridker, Paul M A1 - Sabanayagam, Charumathi A1 - Sale, Michele A1 - Saleheen, Danish A1 - Saltevo, Juha A1 - Schwarz, Peter Eh A1 - Sheu, Wayne H H A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Tabara, Yasuharu A1 - Tuomilehto, Jaakko A1 - van Dam, Rob M A1 - Wilson, James G A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Soranzo, Nicole A1 - Guo, Xiuqing A1 - Roberts, David J A1 - Florez, Jose C A1 - Sladek, Robert A1 - Dupuis, Josée A1 - Morris, Andrew P A1 - Tai, E-Shyong A1 - Selvin, Elizabeth A1 - Rotter, Jerome I A1 - Langenberg, Claudia A1 - Barroso, Inês A1 - Meigs, James B KW - Diabetes Mellitus, Type 2 KW - Genetic Variation KW - Genome-Wide Association Study KW - Glycated Hemoglobin A KW - Humans KW - Phenotype KW - Risk AB -

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

VL - 14 IS - 9 ER - TY - JOUR T1 - Large meta-analysis of genome-wide association studies identifies five loci for lean body mass. JF - Nat Commun Y1 - 2017 A1 - Zillikens, M Carola A1 - Demissie, Serkalem A1 - Hsu, Yi-Hsiang A1 - Yerges-Armstrong, Laura M A1 - Chou, Wen-Chi A1 - Stolk, Lisette A1 - Livshits, Gregory A1 - Broer, Linda A1 - Johnson, Toby A1 - Koller, Daniel L A1 - Kutalik, Zoltán A1 - Luan, Jian'an A1 - Malkin, Ida A1 - Ried, Janina S A1 - Smith, Albert V A1 - Thorleifsson, Gudmar A1 - Vandenput, Liesbeth A1 - Hua Zhao, Jing A1 - Zhang, Weihua A1 - Aghdassi, Ali A1 - Åkesson, Kristina A1 - Amin, Najaf A1 - Baier, Leslie J A1 - Barroso, Inês A1 - Bennett, David A A1 - Bertram, Lars A1 - Biffar, Rainer A1 - Bochud, Murielle A1 - Boehnke, Michael A1 - Borecki, Ingrid B A1 - Buchman, Aron S A1 - Byberg, Liisa A1 - Campbell, Harry A1 - Campos Obanda, Natalia A1 - Cauley, Jane A A1 - Cawthon, Peggy M A1 - Cederberg, Henna A1 - Chen, Zhao A1 - Cho, Nam H A1 - Jin Choi, Hyung A1 - Claussnitzer, Melina A1 - Collins, Francis A1 - Cummings, Steven R A1 - De Jager, Philip L A1 - Demuth, Ilja A1 - Dhonukshe-Rutten, Rosalie A M A1 - Diatchenko, Luda A1 - Eiriksdottir, Gudny A1 - Enneman, Anke W A1 - Erdos, Mike A1 - Eriksson, Johan G A1 - Eriksson, Joel A1 - Estrada, Karol A1 - Evans, Daniel S A1 - Feitosa, Mary F A1 - Fu, Mao A1 - Garcia, Melissa A1 - Gieger, Christian A1 - Girke, Thomas A1 - Glazer, Nicole L A1 - Grallert, Harald A1 - Grewal, Jagvir A1 - Han, Bok-Ghee A1 - Hanson, Robert L A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Hoffman, Eric P A1 - Homuth, Georg A1 - Hsueh, Wen-Chi A1 - Hubal, Monica J A1 - Hubbard, Alan A1 - Huffman, Kim M A1 - Husted, Lise B A1 - Illig, Thomas A1 - Ingelsson, Erik A1 - Ittermann, Till A1 - Jansson, John-Olov A1 - Jordan, Joanne M A1 - Jula, Antti A1 - Karlsson, Magnus A1 - Khaw, Kay-Tee A1 - Kilpeläinen, Tuomas O A1 - Klopp, Norman A1 - Kloth, Jacqueline S L A1 - Koistinen, Heikki A A1 - Kraus, William E A1 - Kritchevsky, Stephen A1 - Kuulasmaa, Teemu A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lahti, Jari A1 - Lang, Thomas A1 - Langdahl, Bente L A1 - Launer, Lenore J A1 - Lee, Jong-Young A1 - Lerch, Markus M A1 - Lewis, Joshua R A1 - Lind, Lars A1 - Lindgren, Cecilia A1 - Liu, Yongmei A1 - Liu, Tian A1 - Liu, Youfang A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Luben, Robert N A1 - Maixner, William A1 - McGuigan, Fiona E A1 - Medina-Gómez, Carolina A1 - Meitinger, Thomas A1 - Melhus, Håkan A1 - Mellström, Dan A1 - Melov, Simon A1 - Michaëlsson, Karl A1 - Mitchell, Braxton D A1 - Morris, Andrew P A1 - Mosekilde, Leif A1 - Newman, Anne A1 - Nielson, Carrie M A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Palotie, Aarno A1 - Parker, Stephen C J A1 - Peacock, Munro A1 - Perola, Markus A1 - Peters, Annette A1 - Polasek, Ozren A1 - Prince, Richard L A1 - Räikkönen, Katri A1 - Ralston, Stuart H A1 - Ripatti, Samuli A1 - Robbins, John A A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Satterfield, Suzanne A1 - Schadt, Eric E A1 - Schipf, Sabine A1 - Scott, Laura A1 - Sehmi, Joban A1 - Shen, Jian A1 - Soo Shin, Chan A1 - Sigurdsson, Gunnar A1 - Smith, Shad A1 - Soranzo, Nicole A1 - Stančáková, Alena A1 - Steinhagen-Thiessen, Elisabeth A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Swart, Karin M A A1 - Tan, Sian-Tsung A1 - Tarnopolsky, Mark A A1 - Thompson, Patricia A1 - Thomson, Cynthia A A1 - Thorsteinsdottir, Unnur A1 - Tikkanen, Emmi A1 - Tranah, Gregory J A1 - Tuomilehto, Jaakko A1 - van Schoor, Natasja M A1 - Verma, Arjun A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wactawski-Wende, Jean A1 - Walker, Mark A1 - Weedon, Michael N A1 - Welch, Ryan A1 - Wichmann, H-Erich A1 - Widen, Elisabeth A1 - Williams, Frances M K A1 - Wilson, James F A1 - Wright, Nicole C A1 - Xie, Weijia A1 - Yu, Lei A1 - Zhou, Yanhua A1 - Chambers, John C A1 - Döring, Angela A1 - van Duijn, Cornelia M A1 - Econs, Michael J A1 - Gudnason, Vilmundur A1 - Kooner, Jaspal S A1 - Psaty, Bruce M A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Ossowski, Vicky A1 - Waterworth, Dawn A1 - Loos, Ruth J F A1 - Karasik, David A1 - Harris, Tamara B A1 - Ohlsson, Claes A1 - Kiel, Douglas P AB -

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10-8) or suggestively genome wide (p < 2.3 × 10-6). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.

VL - 8 IS - 1 ER - TY - JOUR T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. JF - Circ Cardiovasc Genet Y1 - 2017 A1 - Kraja, Aldi T A1 - Cook, James P A1 - Warren, Helen R A1 - Surendran, Praveen A1 - Liu, Chunyu A1 - Evangelou, Evangelos A1 - Manning, Alisa K A1 - Grarup, Niels A1 - Drenos, Fotios A1 - Sim, Xueling A1 - Smith, Albert Vernon A1 - Amin, Najaf A1 - Blakemore, Alexandra I F A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Farmaki, Aliki-Eleni A1 - Fava, Cristiano A1 - Ferreira, Teresa A1 - Herzig, Karl-Heinz A1 - Giri, Ayush A1 - Giulianini, Franco A1 - Grove, Megan L A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Have, Christian T A1 - Havulinna, Aki S A1 - Zhang, He A1 - Jørgensen, Marit E A1 - Käräjämäki, AnneMari A1 - Kooperberg, Charles A1 - Linneberg, Allan A1 - Little, Louis A1 - Liu, Yongmei A1 - Bonnycastle, Lori L A1 - Lu, Yingchang A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Malerba, Giovanni A1 - Marioni, Riccardo E A1 - Mei, Hao A1 - Menni, Cristina A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Palmas, Walter A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Rayner, Nigel William A1 - Riaz, Muhammad A1 - Rice, Ken A1 - Richard, Melissa A A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Stančáková, Alena A1 - Stirrups, Kathleen E A1 - Tragante, Vinicius A1 - Tuomi, Tiinamaija A1 - Tzoulaki, Ioanna A1 - Varga, Tibor V A1 - Weiss, Stefan A1 - Yiorkas, Andrianos M A1 - Young, Robin A1 - Zhang, Weihua A1 - Barnes, Michael R A1 - Cabrera, Claudia P A1 - Gao, He A1 - Boehnke, Michael A1 - Boerwinkle, Eric A1 - Chambers, John C A1 - Connell, John M A1 - Christensen, Cramer K A1 - de Boer, Rudolf A A1 - Deary, Ian J A1 - Dedoussis, George A1 - Deloukas, Panos A1 - Dominiczak, Anna F A1 - Dörr, Marcus A1 - Joehanes, Roby A1 - Edwards, Todd L A1 - Esko, Tõnu A1 - Fornage, Myriam A1 - Franceschini, Nora A1 - Franks, Paul W A1 - Gambaro, Giovanni A1 - Groop, Leif A1 - Hallmans, Göran A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Heikki, Oksa A1 - Ingelsson, Erik A1 - Tuomilehto, Jaakko A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal S A1 - Lakka, Timo A A1 - Langenberg, Claudia A1 - Lind, Lars A1 - Loos, Ruth J F A1 - Laakso, Markku A1 - McCarthy, Mark I A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Morris, Andrew P A1 - Palmer, Colin N A A1 - Pedersen, Oluf A1 - Polasek, Ozren A1 - Poulter, Neil R A1 - Province, Michael A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sever, Peter J A1 - Skaaby, Tea A1 - Stafford, Jeanette M A1 - Starr, John M A1 - van der Harst, Pim A1 - van der Meer, Peter A1 - van Duijn, Cornelia M A1 - Vergnaud, Anne-Claire A1 - Gudnason, Vilmundur A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Willer, Cristen J A1 - Witte, Daniel R A1 - Zeggini, Eleftheria A1 - Saleheen, Danish A1 - Butterworth, Adam S A1 - Danesh, John A1 - Asselbergs, Folkert W A1 - Wain, Louise V A1 - Ehret, Georg B A1 - Chasman, Daniel I A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Lindgren, Cecilia M A1 - Levy, Daniel A1 - Newton-Cheh, Christopher A1 - Munroe, Patricia B A1 - Howson, Joanna M M AB -

BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.

METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.

CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

VL - 10 IS - 5 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 - Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders. JF - Am J Hum Genet Y1 - 2018 A1 - Ligthart, Symen A1 - Vaez, Ahmad A1 - Võsa, Urmo A1 - Stathopoulou, Maria G A1 - de Vries, Paul S A1 - Prins, Bram P A1 - van der Most, Peter J A1 - Tanaka, Toshiko A1 - Naderi, Elnaz A1 - Rose, Lynda M A1 - Wu, Ying A1 - Karlsson, Robert A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Pool, Rene A1 - Zhu, Gu A1 - Mace, Aurelien A1 - Sidore, Carlo A1 - Trompet, Stella A1 - Mangino, Massimo A1 - Sabater-Lleal, Maria A1 - Kemp, John P A1 - Abbasi, Ali A1 - Kacprowski, Tim A1 - Verweij, Niek A1 - Smith, Albert V A1 - Huang, Tao A1 - Marzi, Carola A1 - Feitosa, Mary F A1 - Lohman, Kurt K A1 - Kleber, Marcus E A1 - Milaneschi, Yuri A1 - Mueller, Christian A1 - Huq, Mahmudul A1 - Vlachopoulou, Efthymia A1 - Lyytikäinen, Leo-Pekka A1 - Oldmeadow, Christopher A1 - Deelen, Joris A1 - Perola, Markus A1 - Zhao, Jing Hua A1 - Feenstra, Bjarke A1 - Amini, Marzyeh A1 - Lahti, Jari A1 - Schraut, Katharina E A1 - Fornage, Myriam A1 - Suktitipat, Bhoom A1 - Chen, Wei-Min A1 - Li, Xiaohui A1 - Nutile, Teresa A1 - Malerba, Giovanni A1 - Luan, Jian'an A1 - Bak, Tom A1 - Schork, Nicholas A1 - del Greco M, Fabiola A1 - Thiering, Elisabeth A1 - Mahajan, Anubha A1 - Marioni, Riccardo E A1 - Mihailov, Evelin A1 - Eriksson, Joel A1 - Ozel, Ayse Bilge A1 - Zhang, Weihua A1 - Nethander, Maria A1 - Cheng, Yu-Ching A1 - Aslibekyan, Stella A1 - Ang, Wei A1 - Gandin, Ilaria A1 - Yengo, Loic A1 - Portas, Laura A1 - Kooperberg, Charles A1 - Hofer, Edith A1 - Rajan, Kumar B A1 - Schurmann, Claudia A1 - den Hollander, Wouter A1 - Ahluwalia, Tarunveer S A1 - Zhao, Jing A1 - Draisma, Harmen H M A1 - Ford, Ian A1 - Timpson, Nicholas A1 - Teumer, Alexander A1 - Huang, Hongyan A1 - Wahl, Simone A1 - Liu, Yongmei A1 - Huang, Jie A1 - Uh, Hae-Won A1 - Geller, Frank A1 - Joshi, Peter K A1 - Yanek, Lisa R A1 - Trabetti, Elisabetta A1 - Lehne, Benjamin A1 - Vozzi, Diego A1 - Verbanck, Marie A1 - Biino, Ginevra A1 - Saba, Yasaman A1 - Meulenbelt, Ingrid A1 - O'Connell, Jeff R A1 - Laakso, Markku A1 - Giulianini, Franco A1 - Magnusson, Patrik K E A1 - Ballantyne, Christie M A1 - Hottenga, Jouke Jan A1 - Montgomery, Grant W A1 - Rivadineira, Fernando A1 - Rueedi, Rico A1 - Steri, Maristella A1 - Herzig, Karl-Heinz A1 - Stott, David J A1 - Menni, Cristina A1 - Frånberg, Mattias A1 - St Pourcain, Beate A1 - Felix, Stephan B A1 - Pers, Tune H A1 - Bakker, Stephan J L A1 - Kraft, Peter A1 - Peters, Annette A1 - Vaidya, Dhananjay A1 - Delgado, Graciela A1 - Smit, Johannes H A1 - Großmann, Vera A1 - Sinisalo, Juha A1 - Seppälä, Ilkka A1 - Williams, Stephen R A1 - Holliday, Elizabeth G A1 - Moed, Matthijs A1 - Langenberg, Claudia A1 - Räikkönen, Katri A1 - Ding, Jingzhong A1 - Campbell, Harry A1 - Sale, Michèle M A1 - Chen, Yii-der I A1 - James, Alan L A1 - Ruggiero, Daniela A1 - Soranzo, Nicole A1 - Hartman, Catharina A A1 - Smith, Erin N A1 - Berenson, Gerald S A1 - Fuchsberger, Christian A1 - Hernandez, Dena A1 - Tiesler, Carla M T A1 - Giedraitis, Vilmantas A1 - Liewald, David A1 - Fischer, Krista A1 - Mellström, Dan A1 - Larsson, Anders A1 - Wang, Yunmei A1 - Scott, William R A1 - Lorentzon, Matthias A1 - Beilby, John A1 - Ryan, Kathleen A A1 - Pennell, Craig E A1 - Vuckovic, Dragana A1 - Balkau, Beverly A1 - Concas, Maria Pina A1 - Schmidt, Reinhold A1 - Mendes de Leon, Carlos F A1 - Bottinger, Erwin P A1 - Kloppenburg, Margreet A1 - Paternoster, Lavinia A1 - Boehnke, Michael A1 - Musk, A W A1 - Willemsen, Gonneke A1 - Evans, David M A1 - Madden, Pamela A F A1 - Kähönen, Mika A1 - Kutalik, Zoltán A1 - Zoledziewska, Magdalena A1 - Karhunen, Ville A1 - Kritchevsky, Stephen B A1 - Sattar, Naveed A1 - Lachance, Genevieve A1 - Clarke, Robert A1 - Harris, Tamara B A1 - Raitakari, Olli T A1 - Attia, John R A1 - van Heemst, Diana A1 - Kajantie, Eero A1 - Sorice, Rossella A1 - Gambaro, Giovanni A1 - Scott, Robert A A1 - Hicks, Andrew A A1 - Ferrucci, Luigi A1 - Standl, Marie A1 - Lindgren, Cecilia M A1 - Starr, John M A1 - Karlsson, Magnus A1 - Lind, Lars A1 - Li, Jun Z A1 - Chambers, John C A1 - Mori, Trevor A A1 - de Geus, Eco J C N A1 - Heath, Andrew C A1 - Martin, Nicholas G A1 - Auvinen, Juha A1 - Buckley, Brendan M A1 - de Craen, Anton J M A1 - Waldenberger, Melanie A1 - Strauch, Konstantin A1 - Meitinger, Thomas A1 - Scott, Rodney J A1 - McEvoy, Mark A1 - Beekman, Marian A1 - Bombieri, Cristina A1 - Ridker, Paul M A1 - Mohlke, Karen L A1 - Pedersen, Nancy L A1 - Morrison, Alanna C A1 - Boomsma, Dorret I A1 - Whitfield, John B A1 - Strachan, David P A1 - Hofman, Albert A1 - Vollenweider, Peter A1 - Cucca, Francesco A1 - Jarvelin, Marjo-Riitta A1 - Jukema, J Wouter A1 - Spector, Tim D A1 - Hamsten, Anders A1 - Zeller, Tanja A1 - Uitterlinden, André G A1 - Nauck, Matthias A1 - Gudnason, Vilmundur A1 - Qi, Lu A1 - Grallert, Harald A1 - Borecki, Ingrid B A1 - Rotter, Jerome I A1 - März, Winfried A1 - Wild, Philipp S A1 - Lokki, Marja-Liisa A1 - Boyle, Michael A1 - Salomaa, Veikko A1 - Melbye, Mads A1 - Eriksson, Johan G A1 - Wilson, James F A1 - Penninx, Brenda W J H A1 - Becker, Diane M A1 - Worrall, Bradford B A1 - Gibson, Greg A1 - Krauss, Ronald M A1 - Ciullo, Marina A1 - Zaza, Gianluigi A1 - Wareham, Nicholas J A1 - Oldehinkel, Albertine J A1 - Palmer, Lyle J A1 - Murray, Sarah S A1 - Pramstaller, Peter P A1 - Bandinelli, Stefania A1 - Heinrich, Joachim A1 - Ingelsson, Erik A1 - Deary, Ian J A1 - Mägi, Reedik A1 - Vandenput, Liesbeth A1 - van der Harst, Pim A1 - Desch, Karl C A1 - Kooner, Jaspal S A1 - Ohlsson, Claes A1 - Hayward, Caroline A1 - Lehtimäki, Terho A1 - Shuldiner, Alan R A1 - Arnett, Donna K A1 - Beilin, Lawrence J A1 - Robino, Antonietta A1 - Froguel, Philippe A1 - Pirastu, Mario A1 - Jess, Tine A1 - Koenig, Wolfgang A1 - Loos, Ruth J F A1 - Evans, Denis A A1 - Schmidt, Helena A1 - Smith, George Davey A1 - Slagboom, P Eline A1 - Eiriksdottir, Gudny A1 - Morris, Andrew P A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Nolte, Ilja M A1 - Boerwinkle, Eric A1 - Visvikis-Siest, Sophie A1 - Reiner, Alex P A1 - Gross, Myron A1 - Bis, Joshua C A1 - Franke, Lude A1 - Franco, Oscar H A1 - Benjamin, Emelia J A1 - Chasman, Daniel I A1 - Dupuis, Josée A1 - Snieder, Harold A1 - Dehghan, Abbas A1 - Alizadeh, Behrooz Z AB -

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

VL - 103 IS - 5 ER - TY - JOUR T1 - Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. JF - Nat Commun Y1 - 2018 A1 - Jiang, Xia A1 - O'Reilly, Paul F A1 - Aschard, Hugues A1 - Hsu, Yi-Hsiang A1 - Richards, J Brent A1 - Dupuis, Josée A1 - Ingelsson, Erik A1 - Karasik, David A1 - Pilz, Stefan A1 - Berry, Diane A1 - Kestenbaum, Bryan A1 - Zheng, Jusheng A1 - Luan, Jianan A1 - Sofianopoulou, Eleni A1 - Streeten, Elizabeth A A1 - Albanes, Demetrius A1 - Lutsey, Pamela L A1 - Yao, Lu A1 - Tang, Weihong A1 - Econs, Michael J A1 - Wallaschofski, Henri A1 - Völzke, Henry A1 - Zhou, Ang A1 - Power, Chris A1 - McCarthy, Mark I A1 - Michos, Erin D A1 - Boerwinkle, Eric A1 - Weinstein, Stephanie J A1 - Freedman, Neal D A1 - Huang, Wen-Yi A1 - van Schoor, Natasja M A1 - van der Velde, Nathalie A1 - Groot, Lisette C P G M de A1 - Enneman, Anke A1 - Cupples, L Adrienne A1 - Booth, Sarah L A1 - Vasan, Ramachandran S A1 - Liu, Ching-Ti A1 - Zhou, Yanhua A1 - Ripatti, Samuli A1 - Ohlsson, Claes A1 - Vandenput, Liesbeth A1 - Lorentzon, Mattias A1 - Eriksson, Johan G A1 - Shea, M Kyla A1 - Houston, Denise K A1 - Kritchevsky, Stephen B A1 - Liu, Yongmei A1 - Lohman, Kurt K A1 - Ferrucci, Luigi A1 - Peacock, Munro A1 - Gieger, Christian A1 - Beekman, Marian A1 - Slagboom, Eline A1 - Deelen, Joris A1 - Heemst, Diana van A1 - Kleber, Marcus E A1 - März, Winfried A1 - de Boer, Ian H A1 - Wood, Alexis C A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Robinson-Cohen, Cassianne A1 - den Heijer, Martin A1 - Jarvelin, Marjo-Riitta A1 - Cavadino, Alana A1 - Joshi, Peter K A1 - Wilson, James F A1 - Hayward, Caroline A1 - Lind, Lars A1 - Michaëlsson, Karl A1 - Trompet, Stella A1 - Zillikens, M Carola A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Broer, Linda A1 - Zgaga, Lina A1 - Campbell, Harry A1 - Theodoratou, Evropi A1 - Farrington, Susan M A1 - Timofeeva, Maria A1 - Dunlop, Malcolm G A1 - Valdes, Ana M A1 - Tikkanen, Emmi A1 - Lehtimäki, Terho A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Raitakari, Olli T A1 - Mikkilä, Vera A1 - Ikram, M Arfan A1 - Sattar, Naveed A1 - Jukema, J Wouter A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Forouhi, Nita G A1 - Gundersen, Thomas E A1 - Khaw, Kay-Tee A1 - Butterworth, Adam S A1 - Danesh, John A1 - Spector, Timothy A1 - Wang, Thomas J A1 - Hyppönen, Elina A1 - Kraft, Peter A1 - Kiel, Douglas P AB -

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

VL - 9 IS - 1 ER - TY - JOUR T1 - A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure. JF - Am J Hum Genet Y1 - 2018 A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - de Las Fuentes, Lisa A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Kraja, Aldi T A1 - Schwander, Karen A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Kilpeläinen, Tuomas O A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aslibekyan, Stella A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Dorajoo, Rajkumar A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert Vernon A1 - Tajuddin, Salman M A1 - Tayo, Bamidele O A1 - Warren, Helen R A1 - Zhao, Wei A1 - Zhou, Yanhua A1 - Matoba, Nana A1 - Sofer, Tamar A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Goel, Anuj A1 - Harris, Sarah E A1 - Hartwig, Fernando Pires A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lee, Wen-Jane A1 - Lin, Keng-Hung A1 - 'an Luan, Jian A1 - McKenzie, Colin A A1 - Meian, He A1 - Nelson, Christopher P A1 - Rauramaa, Rainer A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sheu, Wayne H H A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Heming A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Alfred, Tamuno A1 - Amin, Najaf A1 - Arking, Dan A1 - Aung, Tin A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Braund, Peter S A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Cabrera, Claudia P A1 - Cade, Brian A1 - Caizheng, Yu A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Chauhan, Ganesh A1 - Christensen, Kaare A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Connell, John M A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Debette, Stephanie A1 - Dörr, Marcus A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Fisher, Virginia A A1 - Forouhi, Nita G A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gao, He A1 - Gigante, Bruna A1 - Graff, Misa A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Gupta, Preeti A1 - Hagenaars, Saskia P A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hofman, Albert A1 - Howard, Barbara V A1 - Hunt, Steven A1 - Irvin, Marguerite R A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Kaufman, Joel A1 - Kerrison, Nicola D A1 - Khor, Chiea Chuen A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Komulainen, Pirjo A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lim, Sing Hui A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Liu, Kiang A1 - Liu, Yeheng A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Long, Jirong A1 - Louie, Tin A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milani, Lili A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Mosley, Thomas H A1 - Munson, Peter A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nasri, Ubaydah A1 - Norris, Jill M A1 - North, Kari A1 - Ogunniyi, Adesola A1 - Padmanabhan, Sandosh A1 - Palmas, Walter R A1 - Palmer, Nicholette D A1 - Pankow, James S A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Ridker, Paul M A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Sabanayagam, Charumathi A1 - Salako, Babatunde L A1 - Sandow, Kevin A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Seshadri, Sudha A1 - Sever, Peter A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya X A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Forrester, Terrence A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo Lessa A1 - Hung, Yi-Jen A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Lehtimäki, Terho A1 - Liang, Kae-Woei A1 - Magnusson, Patrik K E A1 - Newman, Anne B A1 - Oldehinkel, Albertine J A1 - Pereira, Alexandre C A1 - Redline, Susan A1 - Rettig, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Kamatani, Yoichiro A1 - Laurie, Cathy C A1 - Bouchard, Claude A1 - Cooper, Richard S A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Kritchevsky, Stephen B A1 - Levy, Daniel A1 - O'Connell, Jeff R A1 - Psaty, Bruce M A1 - van Dam, Rob M A1 - Sims, Mario A1 - Arnett, Donna K A1 - Mook-Kanamori, Dennis O A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Province, Michael A A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Chasman, Daniel I AB -

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

VL - 102 IS - 3 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 - Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries. JF - PLoS One Y1 - 2018 A1 - Feitosa, Mary F A1 - Kraja, Aldi T A1 - Chasman, Daniel I A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Li, Changwei A1 - Bentley, Amy R A1 - Brown, Michael R A1 - Schwander, Karen A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Wojczynski, Mary K A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Cai, Qiuyin A1 - Campbell, Archie A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kähönen, Mika A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Luan, Jian'an A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Padmanabhan, Sandosh A1 - Riaz, Muhammad A1 - Rueedi, Rico A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Vitart, Veronique A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Warren, Helen R A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Boerwinkle, Eric A1 - Borecki, Ingrid A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Brumat, Marco A1 - Burke, Gregory L A1 - Canouil, Mickaël A1 - Chakravarti, Aravinda A1 - Charumathi, Sabanayagam A1 - Ida Chen, Yii-Der A1 - Connell, John M A1 - Correa, Adolfo A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Deng, Xuan A1 - Ding, Jingzhong A1 - Duan, Qing A1 - Eaton, Charles B A1 - Ehret, Georg A1 - Eppinga, Ruben N A1 - Evangelou, Evangelos A1 - Faul, Jessica D A1 - Felix, Stephan B A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gigante, Bruna A1 - Gu, C Charles A1 - Gu, Dongfeng A1 - Hagenaars, Saskia P A1 - Hallmans, Göran A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - John, Ulrich A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Lin, Shiow A1 - Liu, Jianjun A1 - Liu, Jingmin A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Nalls, Mike A A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - Norris, Jill M A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Perls, Thomas A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Roll, Kathryn A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rotter, Jerome I A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Schupf, Nicole A1 - Scott, William R A1 - Sever, Peter S A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Sitlani, Colleen M A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - Vollenweider, Peter A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Ya Xing A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Jonas, Jost Bruno A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Kutalik, Zoltán A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Study, Lifelines Cohort A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Polasek, Ozren A1 - Porteous, David J A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Christensen, Kaare A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Pereira, Alexandre C A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Gauderman, W James A1 - Zhu, Xiaofeng A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Rotimi, Charles N A1 - Cupples, L Adrienne A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Kooperberg, Charles A1 - Palmas, Walter A1 - Rice, Kenneth A1 - Morrison, Alanna C A1 - Elliott, Paul A1 - Caulfield, Mark J A1 - Munroe, Patricia B A1 - Rao, Dabeeru C A1 - Province, Michael A A1 - Levy, Daniel AB -

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

VL - 13 IS - 6 ER - TY - JOUR T1 - Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. JF - Nat Genet Y1 - 2018 A1 - Mahajan, Anubha A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Zhao, Wei A1 - Robertson, Neil R A1 - Chu, Audrey Y A1 - Gan, Wei A1 - Kitajima, Hidetoshi A1 - Taliun, Daniel A1 - Rayner, N William A1 - Guo, Xiuqing A1 - Lu, Yingchang A1 - Li, Man A1 - Jensen, Richard A A1 - Hu, Yao A1 - Huo, Shaofeng A1 - Lohman, Kurt K A1 - Zhang, Weihua A1 - Cook, James P A1 - Prins, Bram Peter A1 - Flannick, Jason A1 - Grarup, Niels A1 - Trubetskoy, Vassily Vladimirovich A1 - Kravic, Jasmina A1 - Kim, Young Jin A1 - Rybin, Denis V A1 - Yaghootkar, Hanieh A1 - Müller-Nurasyid, Martina A1 - Meidtner, Karina A1 - Li-Gao, Ruifang A1 - Varga, Tibor V A1 - Marten, Jonathan A1 - Li, Jin A1 - Smith, Albert Vernon A1 - An, Ping A1 - Ligthart, Symen A1 - Gustafsson, Stefan A1 - Malerba, Giovanni A1 - Demirkan, Ayse A1 - Tajes, Juan Fernandez A1 - Steinthorsdottir, Valgerdur A1 - Wuttke, Matthias A1 - Lecoeur, Cécile A1 - Preuss, Michael A1 - Bielak, Lawrence F A1 - Graff, Marielisa A1 - Highland, Heather M A1 - Justice, Anne E A1 - Liu, Dajiang J A1 - Marouli, Eirini A1 - Peloso, Gina Marie A1 - Warren, Helen R A1 - Afaq, Saima A1 - Afzal, Shoaib A1 - Ahlqvist, Emma A1 - Almgren, Peter A1 - Amin, Najaf A1 - Bang, Lia B A1 - Bertoni, Alain G A1 - Bombieri, Cristina A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Burtt, Noel P A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Cho, Yoon Shin A1 - Christensen, Cramer A1 - Eastwood, Sophie V A1 - Eckardt, Kai-Uwe A1 - Fischer, Krista A1 - Gambaro, Giovanni A1 - Giedraitis, Vilmantas A1 - Grove, Megan L A1 - de Haan, Hugoline G A1 - Hackinger, Sophie A1 - Hai, Yang A1 - Han, Sohee A1 - Tybjærg-Hansen, Anne A1 - Hivert, Marie-France A1 - Isomaa, Bo A1 - Jäger, Susanne A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Käräjämäki, AnneMari A1 - Kim, Bong-Jo A1 - Kim, Sung Soo A1 - Koistinen, Heikki A A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Jung-Jin A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Lin, Keng-Hung A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jun A1 - Loh, Marie A1 - Mägi, Reedik A1 - Mamakou, Vasiliki A1 - McKean-Cowdin, Roberta A1 - Nadkarni, Girish A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Ntalla, Ioanna A1 - Peyser, Patricia A A1 - Rathmann, Wolfgang A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rode, Line A1 - Rolandsson, Olov A1 - Schönherr, Sebastian A1 - Selvin, Elizabeth A1 - Small, Kerrin S A1 - Stančáková, Alena A1 - Surendran, Praveen A1 - Taylor, Kent D A1 - Teslovich, Tanya M A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Tin, Adrienne A1 - Tönjes, Anke A1 - Varbo, Anette A1 - Witte, Daniel R A1 - Wood, Andrew R A1 - Yajnik, Pranav A1 - Yao, Jie A1 - Yengo, Loic A1 - Young, Robin A1 - Amouyel, Philippe A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Chowdhury, Rajiv A1 - Collins, Francis S A1 - Dedoussis, George A1 - Dehghan, Abbas A1 - Deloukas, Panos A1 - Ferrario, Marco M A1 - Ferrieres, Jean A1 - Florez, Jose C A1 - Frossard, Philippe A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Howson, Joanna M M A1 - Ingelsson, Martin A1 - Kathiresan, Sekar A1 - Kee, Frank A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lindgren, Cecilia M A1 - Männistö, Satu A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Mohlke, Karen L A1 - Moitry, Marie A1 - Morris, Andrew D A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Orho-Melander, Marju A1 - Owen, Katharine R A1 - Perola, Markus A1 - Peters, Annette A1 - Province, Michael A A1 - Rasheed, Asif A1 - Ridker, Paul M A1 - Rivadineira, Fernando A1 - Rosendaal, Frits R A1 - Rosengren, Anders H A1 - Salomaa, Veikko A1 - Sheu, Wayne H-H A1 - Sladek, Rob A1 - Smith, Blair H A1 - Strauch, Konstantin A1 - Uitterlinden, André G A1 - Varma, Rohit A1 - Willer, Cristen J A1 - Blüher, Matthias A1 - Butterworth, Adam S A1 - Chambers, John Campbell A1 - Chasman, Daniel I A1 - Danesh, John A1 - van Duijn, Cornelia A1 - Dupuis, Josée A1 - Franco, Oscar H A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Grallert, Harald A1 - Groop, Leif A1 - Han, Bok-Ghee A1 - Hansen, Torben A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - Ingelsson, Erik A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kooner, Jaspal Singh A1 - Köttgen, Anna A1 - Kuulasmaa, Kari A1 - Laakso, Markku A1 - Lin, Xu A1 - Lind, Lars A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Marchini, Jonathan A1 - Metspalu, Andres A1 - Mook-Kanamori, Dennis A1 - Nordestgaard, Børge G A1 - Palmer, Colin N A A1 - Pankow, James S A1 - Pedersen, Oluf A1 - Psaty, Bruce M A1 - Rauramaa, Rainer A1 - Sattar, Naveed A1 - Schulze, Matthias B A1 - Soranzo, Nicole A1 - Spector, Timothy D A1 - Stefansson, Kari A1 - Stumvoll, Michael A1 - Thorsteinsdottir, Unnur A1 - Tuomi, Tiinamaija A1 - Tuomilehto, Jaakko A1 - Wareham, Nicholas J A1 - Wilson, James G A1 - Zeggini, Eleftheria A1 - Scott, Robert A A1 - Barroso, Inês A1 - Frayling, Timothy M A1 - Goodarzi, Mark O A1 - Meigs, James B A1 - Boehnke, Michael A1 - Saleheen, Danish A1 - Morris, Andrew P A1 - Rotter, Jerome I A1 - McCarthy, Mark I AB -

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

VL - 50 IS - 4 ER - TY - JOUR T1 - Associations of autozygosity with a broad range of human phenotypes. JF - Nat Commun Y1 - 2019 A1 - Clark, David W A1 - Okada, Yukinori A1 - Moore, Kristjan H S A1 - Mason, Dan A1 - Pirastu, Nicola A1 - Gandin, Ilaria A1 - Mattsson, Hannele A1 - Barnes, Catriona L K A1 - Lin, Kuang A1 - Zhao, Jing Hua A1 - Deelen, Patrick A1 - Rohde, Rebecca A1 - Schurmann, Claudia A1 - Guo, Xiuqing A1 - Giulianini, Franco A1 - Zhang, Weihua A1 - Medina-Gómez, Carolina A1 - Karlsson, Robert A1 - Bao, Yanchun A1 - Bartz, Traci M A1 - Baumbach, Clemens A1 - Biino, Ginevra A1 - Bixley, Matthew J A1 - Brumat, Marco A1 - Chai, Jin-Fang A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Dekker, Annelot M A1 - Eccles, David A A1 - van Eijk, Kristel R A1 - Fuchsberger, Christian A1 - Gao, He A1 - Germain, Marine A1 - Gordon, Scott D A1 - de Haan, Hugoline G A1 - Harris, Sarah E A1 - Hofer, Edith A1 - Huerta-Chagoya, Alicia A1 - Igartua, Catherine A1 - Jansen, Iris E A1 - Jia, Yucheng A1 - Kacprowski, Tim A1 - Karlsson, Torgny A1 - Kleber, Marcus E A1 - Li, Shengchao Alfred A1 - Li-Gao, Ruifang A1 - Mahajan, Anubha A1 - Matsuda, Koichi A1 - Meidtner, Karina A1 - Meng, Weihua A1 - Montasser, May E A1 - van der Most, Peter J A1 - Munz, Matthias A1 - Nutile, Teresa A1 - Palviainen, Teemu A1 - Prasad, Gauri A1 - Prasad, Rashmi B A1 - Priyanka, Tallapragada Divya Sri A1 - Rizzi, Federica A1 - Salvi, Erika A1 - Sapkota, Bishwa R A1 - Shriner, Daniel A1 - Skotte, Line A1 - Smart, Melissa C A1 - Smith, Albert Vernon A1 - van der Spek, Ashley A1 - Spracklen, Cassandra N A1 - Strawbridge, Rona J A1 - Tajuddin, Salman M A1 - Trompet, Stella A1 - Turman, Constance A1 - Verweij, Niek A1 - Viberti, Clara A1 - Wang, Lihua A1 - Warren, Helen R A1 - Wootton, Robyn E A1 - Yanek, Lisa R A1 - Yao, Jie A1 - Yousri, Noha A A1 - Zhao, Wei A1 - Adeyemo, Adebowale A A1 - Afaq, Saima A1 - Aguilar-Salinas, Carlos Alberto A1 - Akiyama, Masato A1 - Albert, Matthew L A1 - Allison, Matthew A A1 - Alver, Maris A1 - Aung, Tin A1 - Azizi, Fereidoun A1 - Bentley, Amy R A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Borja, Judith B A1 - de Borst, Gert J A1 - Bottinger, Erwin P A1 - Broer, Linda A1 - Campbell, Harry A1 - Chanock, Stephen A1 - Chee, Miao-Li A1 - Chen, Guanjie A1 - Chen, Yii-der I A1 - Chen, Zhengming A1 - Chiu, Yen-Feng A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Concas, Maria Pina A1 - Corley, Janie A1 - Cugliari, Giovanni A1 - van Dam, Rob M A1 - Damulina, Anna A1 - Daneshpour, Maryam S A1 - Day, Felix R A1 - Delgado, Graciela E A1 - Dhana, Klodian A1 - Doney, Alexander S F A1 - Dörr, Marcus A1 - Doumatey, Ayo P A1 - Dzimiri, Nduna A1 - Ebenesersdóttir, S Sunna A1 - Elliott, Joshua A1 - Elliott, Paul A1 - Ewert, Ralf A1 - Felix, Janine F A1 - Fischer, Krista A1 - Freedman, Barry I A1 - Girotto, Giorgia A1 - Goel, Anuj A1 - Gögele, Martin A1 - Goodarzi, Mark O A1 - Graff, Mariaelisa A1 - Granot-Hershkovitz, Einat A1 - Grodstein, Francine A1 - Guarrera, Simonetta A1 - Gudbjartsson, Daniel F A1 - Guity, Kamran A1 - Gunnarsson, Bjarni A1 - Guo, Yu A1 - Hagenaars, Saskia P A1 - Haiman, Christopher A A1 - Halevy, Avner A1 - Harris, Tamara B A1 - Hedayati, Mehdi A1 - van Heel, David A A1 - Hirata, Makoto A1 - Höfer, Imo A1 - Hsiung, Chao Agnes A1 - Huang, Jinyan A1 - Hung, Yi-Jen A1 - Ikram, M Arfan A1 - Jagadeesan, Anuradha A1 - Jousilahti, Pekka A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Kerrison, Nicola D A1 - Kessler, Thorsten A1 - Khaw, Kay-Tee A1 - Khor, Chiea Chuen A1 - de Kleijn, Dominique P V A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kraft, Peter A1 - Krämer, Bernhard K A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lawlor, Deborah A A1 - Lee, I-Te A1 - Lee, Wen-Jane A1 - Lerch, Markus M A1 - Li, Liming A1 - Liu, Jianjun A1 - Loh, Marie A1 - London, Stephanie J A1 - Loomis, Stephanie A1 - Lu, Yingchang A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - Manunta, Paolo A1 - Másson, Gísli A1 - Matoba, Nana A1 - Mei, Xue W A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Mezzavilla, Massimo A1 - Milani, Lili A1 - Millwood, Iona Y A1 - Momozawa, Yukihide A1 - Moore, Amy A1 - Morange, Pierre-Emmanuel A1 - Moreno-Macias, Hortensia A1 - Mori, Trevor A A1 - Morrison, Alanna C A1 - Muka, Taulant A1 - Murakami, Yoshinori A1 - Murray, Alison D A1 - de Mutsert, Renée A1 - Mychaleckyj, Josyf C A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Neville, Matt J A1 - Nolte, Ilja M A1 - Ong, Ken K A1 - Orozco, Lorena A1 - Padmanabhan, Sandosh A1 - Pálsson, Gunnar A1 - Pankow, James S A1 - Pattaro, Cristian A1 - Pattie, Alison A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Pramstaller, Peter P A1 - Quintana-Murci, Lluis A1 - Räikkönen, Katri A1 - Ralhan, Sarju A1 - Rao, Dabeeru C A1 - van Rheenen, Wouter A1 - Rich, Stephen S A1 - Ridker, Paul M A1 - Rietveld, Cornelius A A1 - Robino, Antonietta A1 - van Rooij, Frank J A A1 - Ruggiero, Daniela A1 - Saba, Yasaman A1 - Sabanayagam, Charumathi A1 - Sabater-Lleal, Maria A1 - Sala, Cinzia Felicita A1 - Salomaa, Veikko A1 - Sandow, Kevin A1 - Schmidt, Helena A1 - Scott, Laura J A1 - Scott, William R A1 - Sedaghati-Khayat, Bahareh A1 - Sennblad, Bengt A1 - van Setten, Jessica A1 - Sever, Peter J A1 - Sheu, Wayne H-H A1 - Shi, Yuan A1 - Shrestha, Smeeta A1 - Shukla, Sharvari Rahul A1 - Sigurdsson, Jon K A1 - Sikka, Timo Tonis A1 - Singh, Jai Rup A1 - Smith, Blair H A1 - Stančáková, Alena A1 - Stanton, Alice A1 - Starr, John M A1 - Stefansdottir, Lilja A1 - Straker, Leon A1 - Sulem, Patrick A1 - Sveinbjornsson, Gardar A1 - Swertz, Morris A A1 - Taylor, Adele M A1 - Taylor, Kent D A1 - Terzikhan, Natalie A1 - Tham, Yih-Chung A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tillander, Annika A1 - Tracy, Russell P A1 - Tusié-Luna, Teresa A1 - Tzoulaki, Ioanna A1 - Vaccargiu, Simona A1 - Vangipurapu, Jagadish A1 - Veldink, Jan H A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vuoksimaa, Eero A1 - Wakil, Salma M A1 - Waldenberger, Melanie A1 - Wander, Gurpreet S A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Wild, Sarah A1 - Yajnik, Chittaranjan S A1 - Yuan, Jian-Min A1 - Zeng, Lingyao A1 - Zhang, Liang A1 - Zhou, Jie A1 - Amin, Najaf A1 - Asselbergs, Folkert W A1 - Bakker, Stephan J L A1 - Becker, Diane M A1 - Lehne, Benjamin A1 - Bennett, David A A1 - van den Berg, Leonard H A1 - Berndt, Sonja I A1 - Bharadwaj, Dwaipayan A1 - Bielak, Lawrence F A1 - Bochud, Murielle A1 - Boehnke, Mike A1 - Bouchard, Claude A1 - Bradfield, Jonathan P A1 - Brody, Jennifer A A1 - Campbell, Archie A1 - Carmi, Shai A1 - Caulfield, Mark J A1 - Cesarini, David A1 - Chambers, John C A1 - Chandak, Giriraj Ratan A1 - Cheng, Ching-Yu A1 - Ciullo, Marina A1 - Cornelis, Marilyn A1 - Cusi, Daniele A1 - Smith, George Davey A1 - Deary, Ian J A1 - Dorajoo, Rajkumar A1 - van Duijn, Cornelia M A1 - Ellinghaus, David A1 - Erdmann, Jeanette A1 - Eriksson, Johan G A1 - Evangelou, Evangelos A1 - Evans, Michele K A1 - Faul, Jessica D A1 - Feenstra, Bjarke A1 - Feitosa, Mary A1 - Foisy, Sylvain A1 - Franke, Andre A1 - Friedlander, Yechiel A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Gonzalez, Clicerio A1 - Goyette, Philippe A1 - Grant, Struan F A A1 - Griffiths, Lyn R A1 - Groop, Leif A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hakonarson, Hakon A1 - Hamsten, Anders A1 - van der Harst, Pim A1 - Heng, Chew-Kiat A1 - Hicks, Andrew A A1 - Hochner, Hagit A1 - Huikuri, Heikki A1 - Hunt, Steven C A1 - Jaddoe, Vincent W V A1 - De Jager, Philip L A1 - Johannesson, Magnus A1 - Johansson, Asa A1 - Jonas, Jost B A1 - Jukema, J Wouter A1 - Junttila, Juhani A1 - Kaprio, Jaakko A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kumari, Meena A1 - Laakso, Markku A1 - van der Laan, Sander W A1 - Lahti, Jari A1 - Laudes, Matthias A1 - Lea, Rodney A A1 - Lieb, Wolfgang A1 - Lumley, Thomas A1 - Martin, Nicholas G A1 - März, Winfried A1 - Matullo, Giuseppe A1 - McCarthy, Mark I A1 - Medland, Sarah E A1 - Merriman, Tony R A1 - Metspalu, Andres A1 - Meyer, Brian F A1 - Mohlke, Karen L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis A1 - Munroe, Patricia B A1 - North, Kari E A1 - Nyholt, Dale R A1 - O'Connell, Jeffery R A1 - Ober, Carole A1 - Oldehinkel, Albertine J A1 - Palmas, Walter A1 - Palmer, Colin A1 - Pasterkamp, Gerard G A1 - Patin, Etienne A1 - Pennell, Craig E A1 - Perusse, Louis A1 - Peyser, Patricia A A1 - Pirastu, Mario A1 - Polderman, Tinca J C A1 - Porteous, David J A1 - Posthuma, Danielle A1 - Psaty, Bruce M A1 - Rioux, John D A1 - Rivadeneira, Fernando A1 - Rotimi, Charles A1 - Rotter, Jerome I A1 - Rudan, Igor A1 - den Ruijter, Hester M A1 - Sanghera, Dharambir K A1 - Sattar, Naveed A1 - Schmidt, Reinhold A1 - Schulze, Matthias B A1 - Schunkert, Heribert A1 - Scott, Robert A A1 - Shuldiner, Alan R A1 - Sim, Xueling A1 - Small, Neil A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Tai, E-Shyong A1 - Teumer, Alexander A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Trégouët, David-Alexandre A1 - Tuomi, Tiinamaija A1 - Vollenweider, Peter A1 - Wang, Carol A A1 - Weir, David R A1 - Whitfield, John B A1 - Wijmenga, Cisca A1 - Wong, Tien-Yin A1 - Wright, John A1 - Yang, Jingyun A1 - Yu, Lei A1 - Zemel, Babette S A1 - Zonderman, Alan B A1 - Perola, Markus A1 - Magnusson, Patrik K E A1 - Uitterlinden, André G A1 - Kooner, Jaspal S A1 - Chasman, Daniel I A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Franke, Lude A1 - Haley, Chris S A1 - Hayward, Caroline A1 - Walters, Robin G A1 - Perry, John R B A1 - Esko, Tõnu A1 - Helgason, Agnar A1 - Stefansson, Kari A1 - Joshi, Peter K A1 - Kubo, Michiaki A1 - Wilson, James F AB -

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

VL - 10 IS - 1 ER - TY - JOUR T1 - Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions. JF - Am J Epidemiol Y1 - 2019 A1 - de Vries, Paul S A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Winkler, Thomas W A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Kraja, Aldi T A1 - Guo, Xiuqing A1 - Franceschini, Nora A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Deng, Xuan A1 - Dorajoo, Rajkumar A1 - Lohman, Kurt K A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Evangelou, Evangelos A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Gandin, Ilaria A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lee, Joseph H A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Riaz, Muhammad A1 - Said, M Abdullah A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Connell, John M A1 - de Faire, Ulf A1 - de Las Fuentes, Lisa A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - Ding, Jingzhong A1 - Dominiczak, Anna F A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Forrester, Terrence A1 - Franco, Oscar H A1 - Friedlander, Yechiel A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Grove, Megan L A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Howard, Barbara V A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Kammerer, Candace M A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Koistinen, Heikki A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Steve B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lemaitre, Rozenn N A1 - Li, Yize A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Louie, Tin A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Mukamal, Kenneth J A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Sotoodehnia, Nona A1 - O'Connell, Jeff R A1 - Palmer, Nicholette D A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robino, Antonietta A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tan, Nicholas A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Vuckovic, Dragana A1 - Waldenberger, Melanie A1 - Wang, Lihua A1 - Wang, Yujie A1 - Wang, Zhe A1 - Wei, Wen Bin A1 - Williams, Christine A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Yu, Bing A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Deary, Ian J A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Kamatani, Yoichiro A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Penninx, Brenda A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Zheng, Wei A1 - Elliott, Paul A1 - North, Kari E A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Kardia, Sharon L R A1 - Zhu, Xiaofeng A1 - Rotimi, Charles N A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Liu, Jingmin A1 - Rotter, Jerome I A1 - Gauderman, W James A1 - Province, Michael A A1 - Munroe, Patricia B A1 - Rice, Kenneth A1 - Chasman, Daniel I A1 - Cupples, L Adrienne A1 - Rao, Dabeeru C A1 - Morrison, Alanna C AB -

An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. JF - Nat Genet Y1 - 2019 A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Brown, Michael R A1 - Winkler, Thomas W A1 - Kraja, Aldi T A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Chasman, Daniel I A1 - Lim, Elise A1 - Deng, Xuan A1 - Guo, Xiuqing A1 - Liu, Jingmin A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Baker, Jenna A1 - Chen, Guanjie A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Ding, Jingzhong A1 - Dorajoo, Rajkumar A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Zhao, Wei A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Hung, Yi-Jen A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lin, Keng-Hung A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Prins, Bram A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Tzung-Dau A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Xiang, Yong-Bing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Adeyemo, Adebowale A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Arzumanyan, Zorayr A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Cade, Brian E A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Christensen, Kaare A1 - Concas, Maria Pina A1 - Connell, John M A1 - de Las Fuentes, Lisa A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Doumatey, Ayo A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Floyd, James S A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gharib, Sina A A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Ikram, M Arfan A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Liang, Jingjing A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Louie, Tin A1 - Luzzi, Anna A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Tiemeier, Henning A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Heming A1 - Wang, Lan A1 - Wang, Lihua A1 - Wei, Wen Bin A1 - Williams, Christine A A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Young, Kristin A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhou, Jie A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Cooper, Richard S A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Juang, Jyh-Ming Jimmy A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Redline, Susan A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Jun-Sing A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zeggini, Eleftheria A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Province, Michael A A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Rotimi, Charles N A1 - Cupples, L Adrienne AB -

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

VL - 51 IS - 4 ER - TY - JOUR T1 - Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity. JF - Nat Commun Y1 - 2019 A1 - Kilpeläinen, Tuomas O A1 - Bentley, Amy R A1 - Noordam, Raymond A1 - Sung, Yun Ju A1 - Schwander, Karen A1 - Winkler, Thomas W A1 - Jakupović, Hermina A1 - Chasman, Daniel I A1 - Manning, Alisa A1 - Ntalla, Ioanna A1 - Aschard, Hugues A1 - Brown, Michael R A1 - de Las Fuentes, Lisa A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Vojinovic, Dina A1 - Aslibekyan, Stella A1 - Feitosa, Mary F A1 - Kho, Minjung A1 - Musani, Solomon K A1 - Richard, Melissa A1 - Wang, Heming A1 - Wang, Zhe A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Campbell, Archie A1 - Dorajoo, Rajkumar A1 - Fisher, Virginia A1 - Hartwig, Fernando P A1 - Horimoto, Andrea R V R A1 - Li, Changwei A1 - Lohman, Kurt K A1 - Marten, Jonathan A1 - Sim, Xueling A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Alver, Maris A1 - Amini, Marzyeh A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Graff, Mariaelisa A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Jackson, Anne U A1 - Zhao, Jing Hua A1 - Kraja, Aldi T A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Rueedi, Rico A1 - Stringham, Heather M A1 - Takeuchi, Fumihiko A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Verweij, Niek A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Li, Xiaoyin A1 - Yanek, Lisa R A1 - Amin, Najaf A1 - Arnett, Donna K A1 - Boerwinkle, Eric A1 - Brumat, Marco A1 - Cade, Brian A1 - Canouil, Mickaël A1 - Chen, Yii-Der Ida A1 - Concas, Maria Pina A1 - Connell, John A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Demirkan, Ayse A1 - Ding, Jingzhong A1 - Eaton, Charles B A1 - Faul, Jessica D A1 - Friedlander, Yechiel A1 - Gabriel, Kelley P A1 - Ghanbari, Mohsen A1 - Giulianini, Franco A1 - Gu, Chi Charles A1 - Gu, Dongfeng A1 - Harris, Tamara B A1 - He, Jiang A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hunt, Steven C A1 - Ikram, M Arfan A1 - Jonas, Jost B A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kutalik, Zoltán A1 - Kuusisto, Johanna A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Leander, Karin A1 - Lemaitre, Rozenn N A1 - Lewis, Cora E A1 - Liang, Jingjing A1 - Liu, Jianjun A1 - Mägi, Reedik A1 - Manichaikul, Ani A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Mohlke, Karen L A1 - Mosley, Thomas H A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nang, Ei-Ei Khaing A1 - Nelson, Christopher P A1 - Nona, Sotoodehnia A1 - Norris, Jill M A1 - Nwuba, Chiamaka Vivian A1 - O'Connell, Jeff A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pazoki, Raha A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Porteous, David J A1 - Poveda, Alaitz A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Risch, Neil A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rudan, Igor A1 - Schreiner, Pamela J A1 - Scott, Robert A A1 - Sidney, Stephen S A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Sofer, Tamar A1 - Starr, John M A1 - Sternfeld, Barbara A1 - Strauch, Konstantin A1 - Tang, Hua A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Tuomilehto, Jaakko A1 - Uitterlinden, André G A1 - van der Ende, M Yldau A1 - van Heemst, Diana A1 - Voortman, Trudy A1 - Waldenberger, Melanie A1 - Wennberg, Patrik A1 - Wilson, Gregory A1 - Xiang, Yong-Bing A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Samani, Nilesh J A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - van Vliet-Ostaptchouk, Jana V A1 - Vollenweider, Peter A1 - Wagenknecht, Lynne E A1 - Wang, Ya X A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Evans, Michele K A1 - Franks, Paul W A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kelly, Tanika N A1 - Liu, Yongmei A1 - North, Kari E A1 - Pereira, Alexandre C A1 - Ridker, Paul M A1 - Tai, E Shyong A1 - van Dam, Rob M A1 - Fox, Ervin R A1 - Kardia, Sharon L R A1 - Liu, Ching-Ti A1 - Mook-Kanamori, Dennis O A1 - Province, Michael A A1 - Redline, Susan A1 - van Duijn, Cornelia M A1 - Rotter, Jerome I A1 - Kooperberg, Charles B A1 - Gauderman, W James A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Fornage, Myriam A1 - Cupples, L Adrienne A1 - Rotimi, Charles N A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Loos, Ruth J F KW - Adolescent KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Asian Continental Ancestry Group KW - Brazil KW - Calcium-Binding Proteins KW - Cholesterol KW - Cholesterol, HDL KW - Cholesterol, LDL KW - European Continental Ancestry Group KW - Exercise KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Hispanic Americans KW - Humans KW - LIM-Homeodomain Proteins KW - Lipid Metabolism KW - Lipids KW - Male KW - Membrane Proteins KW - Microtubule-Associated Proteins KW - Middle Aged KW - Muscle Proteins KW - Nerve Tissue Proteins KW - Transcription Factors KW - Triglycerides KW - Young Adult AB -

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

VL - 10 IS - 1 ER - TY - JOUR T1 - Trans-ethnic association study of blood pressure determinants in over 750,000 individuals. JF - Nat Genet Y1 - 2019 A1 - Giri, Ayush A1 - Hellwege, Jacklyn N A1 - Keaton, Jacob M A1 - Park, Jihwan A1 - Qiu, Chengxiang A1 - Warren, Helen R A1 - Torstenson, Eric S A1 - Kovesdy, Csaba P A1 - Sun, Yan V A1 - Wilson, Otis D A1 - Robinson-Cohen, Cassianne A1 - Roumie, Christianne L A1 - Chung, Cecilia P A1 - Birdwell, Kelly A A1 - Damrauer, Scott M A1 - DuVall, Scott L A1 - Klarin, Derek A1 - Cho, Kelly A1 - Wang, Yu A1 - Evangelou, Evangelos A1 - Cabrera, Claudia P A1 - Wain, Louise V A1 - Shrestha, Rojesh A1 - Mautz, Brian S A1 - Akwo, Elvis A A1 - Sargurupremraj, Muralidharan A1 - Debette, Stephanie A1 - Boehnke, Michael A1 - Scott, Laura J A1 - Luan, Jian'an A1 - Zhao, Jing-Hua A1 - Willems, Sara M A1 - Thériault, Sébastien A1 - Shah, Nabi A1 - Oldmeadow, Christopher A1 - Almgren, Peter A1 - Li-Gao, Ruifang A1 - Verweij, Niek A1 - Boutin, Thibaud S A1 - Mangino, Massimo A1 - Ntalla, Ioanna A1 - Feofanova, Elena A1 - Surendran, Praveen A1 - Cook, James P A1 - Karthikeyan, Savita A1 - Lahrouchi, Najim A1 - Liu, Chunyu A1 - Sepúlveda, Nuno A1 - Richardson, Tom G A1 - Kraja, Aldi A1 - Amouyel, Philippe A1 - Farrall, Martin A1 - Poulter, Neil R A1 - Laakso, Markku A1 - Zeggini, Eleftheria A1 - Sever, Peter A1 - Scott, Robert A A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Conen, David A1 - Palmer, Colin Neil Alexander A1 - Attia, John A1 - Chasman, Daniel I A1 - Ridker, Paul M A1 - Melander, Olle A1 - Mook-Kanamori, Dennis Owen A1 - Harst, Pim van der A1 - Cucca, Francesco A1 - Schlessinger, David A1 - Hayward, Caroline A1 - Spector, Tim D A1 - Jarvelin, Marjo-Riitta A1 - Hennig, Branwen J A1 - Timpson, Nicholas J A1 - Wei, Wei-Qi A1 - Smith, Joshua C A1 - Xu, Yaomin A1 - Matheny, Michael E A1 - Siew, Edward E A1 - Lindgren, Cecilia A1 - Herzig, Karl-Heinz A1 - Dedoussis, George A1 - Denny, Joshua C A1 - Psaty, Bruce M A1 - Howson, Joanna M M A1 - Munroe, Patricia B A1 - Newton-Cheh, Christopher A1 - Caulfield, Mark J A1 - Elliott, Paul A1 - Gaziano, J Michael A1 - Concato, John A1 - Wilson, Peter W F A1 - Tsao, Philip S A1 - Velez Edwards, Digna R A1 - Susztak, Katalin A1 - O'Donnell, Christopher J A1 - Hung, Adriana M A1 - Edwards, Todd L AB -

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

VL - 51 IS - 1 ER - TY - JOUR T1 - Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity. JF - Diabetes Y1 - 2020 A1 - Yaghootkar, Hanieh A1 - Zhang, Yiying A1 - Spracklen, Cassandra N A1 - Karaderi, Tugce A1 - Huang, Lam Opal A1 - Bradfield, Jonathan A1 - Schurmann, Claudia A1 - Fine, Rebecca S A1 - Preuss, Michael H A1 - Kutalik, Zoltán A1 - Wittemans, Laura Bl A1 - Lu, Yingchang A1 - Metz, Sophia A1 - Willems, Sara M A1 - Li-Gao, Ruifang A1 - Grarup, Niels A1 - Wang, Shuai A1 - Molnos, Sophie A1 - Sandoval-Zárate, América A A1 - Nalls, Mike A A1 - Lange, Leslie A A1 - Haesser, Jeffrey A1 - Guo, Xiuqing A1 - Lyytikäinen, Leo-Pekka A1 - Feitosa, Mary F A1 - Sitlani, Colleen M A1 - Venturini, Cristina A1 - Mahajan, Anubha A1 - Kacprowski, Tim A1 - Wang, Carol A A1 - Chasman, Daniel I A1 - Amin, Najaf A1 - Broer, Linda A1 - Robertson, Neil A1 - Young, Kristin L A1 - Allison, Matthew A1 - Auer, Paul L A1 - Blüher, Matthias A1 - Borja, Judith B A1 - Bork-Jensen, Jette A1 - Carrasquilla, Germán D A1 - Christofidou, Paraskevi A1 - Demirkan, Ayse A1 - Doege, Claudia A A1 - Garcia, Melissa E A1 - Graff, Mariaelisa A1 - Guo, Kaiying A1 - Hakonarson, Hakon A1 - Hong, Jaeyoung A1 - Ida Chen, Yii-Der A1 - Jackson, Rebecca A1 - Jakupović, Hermina A1 - Jousilahti, Pekka A1 - Justice, Anne E A1 - Kähönen, Mika A1 - Kizer, Jorge R A1 - Kriebel, Jennifer A1 - LeDuc, Charles A A1 - Li, Jin A1 - Lind, Lars A1 - Luan, Jian'an A1 - Mackey, David A1 - Mangino, Massimo A1 - Männistö, Satu A1 - Martin Carli, Jayne F A1 - Medina-Gómez, Carolina A1 - Mook-Kanamori, Dennis O A1 - Morris, Andrew P A1 - de Mutsert, Renée A1 - Nauck, Matthias A1 - Nedeljkovic, Ivana A1 - Pennell, Craig E A1 - Pradhan, Arund D A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Scott, Robert A A1 - Skaaby, Tea A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Wu, Ying A1 - Yao, Jie A1 - Walker, Mark A1 - North, Kari E A1 - Kovacs, Peter A1 - Ikram, M Arfan A1 - van Duijn, Cornelia M A1 - Ridker, Paul M A1 - Lye, Stephen A1 - Homuth, Georg A1 - Ingelsson, Erik A1 - Spector, Tim D A1 - McKnight, Barbara A1 - Province, Michael A A1 - Lehtimäki, Terho A1 - Adair, Linda S A1 - Rotter, Jerome I A1 - Reiner, Alexander P A1 - Wilson, James G A1 - Harris, Tamara B A1 - Ripatti, Samuli A1 - Grallert, Harald A1 - Meigs, James B A1 - Salomaa, Veikko A1 - Hansen, Torben A1 - Willems van Dijk, Ko A1 - Wareham, Nicholas J A1 - Grant, Struan Fa A1 - Langenberg, Claudia A1 - Frayling, Timothy M A1 - Lindgren, Cecilia M A1 - Mohlke, Karen L A1 - Leibel, Rudolph L A1 - Loos, Ruth Jf A1 - Kilpeläinen, Tuomas O AB -

Leptin influences food intake by informing the brain about the status of body fat stores. Rare mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in , and , and one intergenic variant near The missense variant Val94Met (rs17151919) in was common in individuals of African ancestry only and its association with lower leptin concentrations was specific to this ancestry (P=2x10, n=3,901). Using analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting leptin regulates early adiposity.

ER - TY - JOUR T1 - Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. JF - Nat Commun Y1 - 2021 A1 - Harris, William S A1 - Tintle, Nathan L A1 - Imamura, Fumiaki A1 - Qian, Frank A1 - Korat, Andres V Ardisson A1 - Marklund, Matti A1 - Djoussé, Luc A1 - Bassett, Julie K A1 - Carmichael, Pierre-Hugues A1 - Chen, Yun-Yu A1 - Hirakawa, Yoichiro A1 - Küpers, Leanne K A1 - Laguzzi, Federica A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Samieri, Cecilia A1 - Senn, Mackenzie K A1 - Shi, Peilin A1 - Virtanen, Jyrki K A1 - Brouwer, Ingeborg A A1 - Chien, Kuo-Liong A1 - Eiriksdottir, Gudny A1 - Forouhi, Nita G A1 - Geleijnse, Johanna M A1 - Giles, Graham G A1 - Gudnason, Vilmundur A1 - Helmer, Catherine A1 - Hodge, Allison A1 - Jackson, Rebecca A1 - Khaw, Kay-Tee A1 - Laakso, Markku A1 - Lai, Heidi A1 - Laurin, Danielle A1 - Leander, Karin A1 - Lindsay, Joan A1 - Micha, Renata A1 - Mursu, Jaako A1 - Ninomiya, Toshiharu A1 - Post, Wendy A1 - Psaty, Bruce M A1 - Riserus, Ulf A1 - Robinson, Jennifer G A1 - Shadyab, Aladdin H A1 - Snetselaar, Linda A1 - Sala-Vila, Aleix A1 - Sun, Yangbo A1 - Steffen, Lyn M A1 - Tsai, Michael Y A1 - Wareham, Nicholas J A1 - Wood, Alexis C A1 - Wu, Jason H Y A1 - Hu, Frank A1 - Sun, Qi A1 - Siscovick, David S A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Fatty Acids, Omega-3 KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Middle Aged KW - Mortality, Premature KW - Prospective Studies KW - Protective Factors KW - Risk Factors AB -

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

VL - 12 IS - 1 ER - TY - JOUR T1 - Genetic insights into biological mechanisms governing human ovarian ageing. JF - Nature Y1 - 2021 A1 - Ruth, Katherine S A1 - Day, Felix R A1 - Hussain, Jazib A1 - Martínez-Marchal, Ana A1 - Aiken, Catherine E A1 - Azad, Ajuna A1 - Thompson, Deborah J A1 - Knoblochova, Lucie A1 - Abe, Hironori A1 - Tarry-Adkins, Jane L A1 - Gonzalez, Javier Martin A1 - Fontanillas, Pierre A1 - Claringbould, Annique A1 - Bakker, Olivier B A1 - Sulem, Patrick A1 - Walters, Robin G A1 - Terao, Chikashi A1 - Turon, Sandra A1 - Horikoshi, Momoko A1 - Lin, Kuang A1 - Onland-Moret, N Charlotte A1 - Sankar, Aditya A1 - Hertz, Emil Peter Thrane A1 - Timshel, Pascal N A1 - Shukla, Vallari A1 - Borup, Rehannah A1 - Olsen, Kristina W A1 - Aguilera, Paula A1 - Ferrer-Roda, Mònica A1 - Huang, Yan A1 - Stankovic, Stasa A1 - Timmers, Paul R H J A1 - Ahearn, Thomas U A1 - Alizadeh, Behrooz Z A1 - Naderi, Elnaz A1 - Andrulis, Irene L A1 - Arnold, Alice M A1 - Aronson, Kristan J A1 - Augustinsson, Annelie A1 - Bandinelli, Stefania A1 - Barbieri, Caterina M A1 - Beaumont, Robin N A1 - Becher, Heiko A1 - Beckmann, Matthias W A1 - Benonisdottir, Stefania A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Boomsma, Dorret I A1 - Bowker, Nicholas A1 - Brody, Jennifer A A1 - Broer, Linda A1 - Buring, Julie E A1 - Campbell, Archie A1 - Campbell, Harry A1 - Castelao, Jose E A1 - Catamo, Eulalia A1 - Chanock, Stephen J A1 - Chenevix-Trench, Georgia A1 - Ciullo, Marina A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cox, Angela A1 - Crisponi, Laura A1 - Cross, Simon S A1 - Cucca, Francesco A1 - Czene, Kamila A1 - Smith, George Davey A1 - de Geus, Eco J C N A1 - de Mutsert, Renée A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Dunning, Alison M A1 - Dwek, Miriam A1 - Eriksson, Mikael A1 - Esko, Tõnu A1 - Fasching, Peter A A1 - Faul, Jessica D A1 - Ferrucci, Luigi A1 - Franceschini, Nora A1 - Frayling, Timothy M A1 - Gago-Dominguez, Manuela A1 - Mezzavilla, Massimo A1 - García-Closas, Montserrat A1 - Gieger, Christian A1 - Giles, Graham G A1 - Grallert, Harald A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guénel, Pascal A1 - Haiman, Christopher A A1 - Håkansson, Niclas A1 - Hall, Per A1 - Hayward, Caroline A1 - He, Chunyan A1 - He, Wei A1 - Heiss, Gerardo A1 - Høffding, Miya K A1 - Hopper, John L A1 - Hottenga, Jouke J A1 - Hu, Frank A1 - Hunter, David A1 - Ikram, Mohammad A A1 - Jackson, Rebecca D A1 - Joaquim, Micaella D R A1 - John, Esther M A1 - Joshi, Peter K A1 - Karasik, David A1 - Kardia, Sharon L R A1 - Kartsonaki, Christiana A1 - Karlsson, Robert A1 - Kitahara, Cari M A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Kraft, Peter A1 - Kurian, Allison W A1 - Kutalik, Zoltán A1 - La Bianca, Martina A1 - Lachance, Genevieve A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Lawlor, Deborah A A1 - Le Marchand, Loïc A1 - Li, Jingmei A1 - Lindblom, Annika A1 - Lindström, Sara A1 - Lindstrom, Tricia A1 - Linet, Martha A1 - Liu, Yongmei A1 - Liu, Simin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mannermaa, Arto A1 - Marco, Brumat A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mbarek, Hamdi A1 - McKnight, Barbara A1 - Medland, Sarah E A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Metspalu, Andres A1 - Milani, Lili A1 - Milne, Roger L A1 - Montgomery, Grant W A1 - Mook-Kanamori, Dennis O A1 - Mulas, Antonella A1 - Mulligan, Anna M A1 - Murray, Alison A1 - Nalls, Mike A A1 - Newman, Anne A1 - Noordam, Raymond A1 - Nutile, Teresa A1 - Nyholt, Dale R A1 - Olshan, Andrew F A1 - Olsson, Håkan A1 - Painter, Jodie N A1 - Patel, Alpa V A1 - Pedersen, Nancy L A1 - Perjakova, Natalia A1 - Peters, Annette A1 - Peters, Ulrike A1 - Pharoah, Paul D P A1 - Polasek, Ozren A1 - Porcu, Eleonora A1 - Psaty, Bruce M A1 - Rahman, Iffat A1 - Rennert, Gad A1 - Rennert, Hedy S A1 - Ridker, Paul M A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rossouw, Jacques A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Saloustros, Emmanouil A1 - Sandler, Dale P A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Sarnowski, Chloe A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schoemaker, Minouk J A1 - Schraut, Katharina E A1 - Scott, Christopher A1 - Shekari, Saleh A1 - Shrikhande, Amruta A1 - Smith, Albert V A1 - Smith, Blair H A1 - Smith, Jennifer A A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Spector, Tim D A1 - Spinelli, John J A1 - Stampfer, Meir A1 - Stöckl, Doris A1 - van Meurs, Joyce B J A1 - Strauch, Konstantin A1 - Styrkarsdottir, Unnur A1 - Swerdlow, Anthony J A1 - Tanaka, Toshiko A1 - Teras, Lauren R A1 - Teumer, Alexander A1 - Þorsteinsdottir, Unnur A1 - Timpson, Nicholas J A1 - Toniolo, Daniela A1 - Traglia, Michela A1 - Troester, Melissa A A1 - Truong, Thérèse A1 - Tyrrell, Jessica A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Vachon, Celine M A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Wang, Qin A1 - Wareham, Nicholas J A1 - Weinberg, Clarice R A1 - Weir, David R A1 - Wilcox, Amber N A1 - van Dijk, Ko Willems A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wolk, Alicja A1 - Wood, Andrew R A1 - Zhao, Wei A1 - Zygmunt, Marek A1 - Chen, Zhengming A1 - Li, Liming A1 - Franke, Lude A1 - Burgess, Stephen A1 - Deelen, Patrick A1 - Pers, Tune H A1 - Grøndahl, Marie Louise A1 - Andersen, Claus Yding A1 - Pujol, Anna A1 - Lopez-Contreras, Andres J A1 - Daniel, Jeremy A A1 - Stefansson, Kari A1 - Chang-Claude, Jenny A1 - van der Schouw, Yvonne T A1 - Lunetta, Kathryn L A1 - Chasman, Daniel I A1 - Easton, Douglas F A1 - Visser, Jenny A A1 - Ozanne, Susan E A1 - Namekawa, Satoshi H A1 - Solc, Petr A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Hoffmann, Eva R A1 - Murray, Anna A1 - Roig, Ignasi A1 - Perry, John R B AB -

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.

VL - 596 IS - 7872 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 - Association of omega 3 polyunsaturated fatty acids with incident chronic kidney disease: pooled analysis of 19 cohorts. JF - BMJ Y1 - 2023 A1 - Ong, Kwok Leung A1 - Marklund, Matti A1 - Huang, Liping A1 - Rye, Kerry-Anne A1 - Hui, Nicholas A1 - Pan, Xiong-Fei A1 - Rebholz, Casey M A1 - Kim, Hyunju A1 - Steffen, Lyn M A1 - van Westing, Anniek C A1 - Geleijnse, Johanna M A1 - Hoogeveen, Ellen K A1 - Chen, Yun-Yu A1 - Chien, Kuo-Liong A1 - Fretts, Amanda M A1 - Lemaitre, Rozenn N A1 - Imamura, Fumiaki A1 - Forouhi, Nita G A1 - Wareham, Nicholas J A1 - Birukov, Anna A1 - Jäger, Susanne A1 - Kuxhaus, Olga A1 - Schulze, Matthias B A1 - de Mello, Vanessa Derenji A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - Lindström, Jaana A1 - Tintle, Nathan A1 - Harris, William S A1 - Yamasaki, Keisuke A1 - Hirakawa, Yoichiro A1 - Ninomiya, Toshiharu A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Virtanen, Jyrki K A1 - Voutilainen, Ari A1 - Jayasena, Tharusha A1 - Thalamuthu, Anbupalam A1 - Poljak, Anne A1 - Bustamante, Sonia A1 - Sachdev, Perminder S A1 - Senn, Mackenzie K A1 - Rich, Stephen S A1 - Tsai, Michael Y A1 - Wood, Alexis C A1 - Laakso, Markku A1 - Lankinen, Maria A1 - Yang, Xiaowei A1 - Sun, Liang A1 - Li, Huaixing A1 - Lin, Xu A1 - Nowak, Christoph A1 - Arnlöv, Johan A1 - Riserus, Ulf A1 - Lind, Lars A1 - Le Goff, Mélanie A1 - Samieri, Cecilia A1 - Helmer, Catherine A1 - Qian, Frank A1 - Micha, Renata A1 - Tin, Adrienne A1 - Köttgen, Anna A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Mozaffarian, Dariush A1 - Wu, Jason HY KW - alpha-Linolenic Acid KW - Fatty Acids, Omega-3 KW - Fatty Acids, Unsaturated KW - Humans KW - Middle Aged KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

OBJECTIVE: To assess the prospective associations of circulating levels of omega 3 polyunsaturated fatty acid (n-3 PUFA) biomarkers (including plant derived α linolenic acid and seafood derived eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid) with incident chronic kidney disease (CKD).

DESIGN: Pooled analysis.

DATA SOURCES: A consortium of 19 studies from 12 countries identified up to May 2020.

STUDY SELECTION: Prospective studies with measured n-3 PUFA biomarker data and incident CKD based on estimated glomerular filtration rate.

DATA EXTRACTION AND SYNTHESIS: Each participating cohort conducted de novo analysis with prespecified and consistent exposures, outcomes, covariates, and models. The results were pooled across cohorts using inverse variance weighted meta-analysis.

MAIN OUTCOME MEASURES: Primary outcome of incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m. In a sensitivity analysis, incident CKD was defined as new onset estimated glomerular filtration rate <60 mL/min/1.73 m and <75% of baseline rate.

RESULTS: 25 570 participants were included in the primary outcome analysis and 4944 (19.3%) developed incident CKD during follow-up (weighted median 11.3 years). In multivariable adjusted models, higher levels of total seafood n-3 PUFAs were associated with a lower incident CKD risk (relative risk per interquintile range 0.92, 95% confidence interval 0.86 to 0.98; P=0.009, I=9.9%). In categorical analyses, participants with total seafood n-3 PUFA level in the highest fifth had 13% lower risk of incident CKD compared with those in the lowest fifth (0.87, 0.80 to 0.96; P=0.005, I=0.0%). Plant derived α linolenic acid levels were not associated with incident CKD (1.00, 0.94 to 1.06; P=0.94, I=5.8%). Similar results were obtained in the sensitivity analysis. The association appeared consistent across subgroups by age (≥60 <60 years), estimated glomerular filtration rate (60-89 ≥90 mL/min/1.73 m), hypertension, diabetes, and coronary heart disease at baseline.

CONCLUSIONS: Higher seafood derived n-3 PUFA levels were associated with lower risk of incident CKD, although this association was not found for plant derived n-3 PUFAs. These results support a favourable role for seafood derived n-3 PUFAs in preventing CKD.

VL - 380 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. JF - medRxiv Y1 - 2023 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 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Ana Luiza de, S V Arruda 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 - 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 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Danesh, John A1 - Das, Swapan K A1 - Janaka de Silva, H 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 - 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 - 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 - Lithgart, 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 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D 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 - 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 - 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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 - TY - JOUR T1 - Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies. JF - Circulation Y1 - 2024 A1 - Laguzzi, Federica A1 - Åkesson, Agneta A1 - Marklund, Matti A1 - Qian, Frank A1 - Gigante, Bruna A1 - Bartz, Traci M A1 - Bassett, Julie K A1 - Birukov, Anna A1 - Campos, Hannia A1 - Hirakawa, Yoichiro A1 - Imamura, Fumiaki A1 - Jäger, Susanne A1 - Lankinen, Maria A1 - Murphy, Rachel A A1 - Senn, Mackenzie A1 - Tanaka, Toshiko A1 - Tintle, Nathan A1 - Virtanen, Jyrki K A1 - Yamagishi, Kazumasa A1 - Allison, Matthew A1 - Brouwer, Ingeborg A A1 - de Faire, Ulf A1 - Eiriksdottir, Gudny A1 - Ferrucci, Luigi A1 - Forouhi, Nita G A1 - Geleijnse, Johanna M A1 - Hodge, Allison M A1 - Kimura, Hitomi A1 - Laakso, Markku A1 - Riserus, Ulf A1 - van Westing, Anniek C A1 - Bandinelli, Stefania A1 - Baylin, Ana A1 - Giles, Graham G A1 - Gudnason, Vilmundur A1 - Iso, Hiroyasu A1 - Lemaitre, Rozenn N A1 - Ninomiya, Toshiharu A1 - Post, Wendy S A1 - Psaty, Bruce M A1 - Salonen, Jukka T A1 - Schulze, Matthias B A1 - Tsai, Michael Y A1 - Uusitupa, Matti A1 - Wareham, Nicholas J A1 - Oh, Seung-Won A1 - Wood, Alexis C A1 - Harris, William S A1 - Siscovick, David A1 - Mozaffarian, Dariush A1 - Leander, Karin KW - Animals KW - Biomarkers KW - Cardiovascular Diseases KW - Docosahexaenoic Acids KW - Fatty Acids, Omega-3 KW - Risk Factors AB -

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.

METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.

RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.

CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

VL - 149 IS - 4 ER -