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Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

2012; Elsevier BV; Volume: 90; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2011.12.022

1537-6605

Richa Saxena, Clara C. Elbers, Yiran Guo, Inga Peter, Tom R. Gaunt, Jessica L. Mega, Matthew B. Lanktree, Archana Tare, Berta Almoguera Castillo, Leslie A. Lange, Toby Johnson, Marcel Bruinenberg, Diane Gilbert‐Diamond, Ramakrishnan Rajagopalan, Benjamin F. Voight, Ashok Balasubramanyam, John Barnard, Florianne Bauer, Jens Baumert, Tushar Bhangale, Bernhard Böhm, Peter S. Braund, Paul R. Burton, Hareesh Chandrupatla, Robert Clarke, Rhonda M. Cooper‐DeHoff, Errol D. Crook, George Davey Smith, Ian N.M. Day, Anthonius de Boer, Mark de Groot, Fotios Drenos, Jane F. Ferguson, Caroline S. Fox, Clement E. Furlong, Quince Gibson, Christian Gieger, L. A. Gilhuijs-Pederson, Joseph Glessner, Anuj Goel, Yan Gong, Struan F.A. Grant, Diederick E. Grobbee, Claire E. Hastie, Steve E. Humphries, Cecilia E. Kim, Mika Kivimäki, Marcus E. Kleber, Christa Meisinger, Meena Kumari, Taimour Langaee, Debbie A. Lawlor, Mingyao Li, Maximilian T. Lobmeyer, Anke H. Maitland‐van der Zee, Matthijs F.L. Meijs, Cliona Molony, David A. Morrow, Gurunathan Murugesan, Solomon K. Musani, Christopher P. Nelson, Stephen Newhouse, Jeffery R. O’Connell, Sandosh Padmanabhan, Jutta Palmen, Sanjay R. Patel, Carl J. Pepine, Mary Pettinger, Thomas S. Price, Suzanne Rafelt, Jane Ranchalis, Asif Rasheed, Elisabeth A. Rosenthal, Ingo Ruczinski, Sonia Shah, Haiqing Shen, Günther Silbernagel, Erin N. Smith, Annemieke W.M. Spijkerman, Alice Stanton, Michael W. Steffes, Barbara Thorand, Mieke D. Trip, Pim van der Harst, Daphne L. van der A, Erik P.A. van Iperen, Jessica van Setten, Jana V. van Vliet‐Ostaptchouk, Niek Verweij, Bruce H. R. Wolffenbuttel, Taylor Young, Mohammad Hadi Zafarmand, Joseph M. Zmuda, Michael Boehnke, David Altshuler, Mark I. McCarthy, W.H. Linda Kao, James S. Pankow, Thomas P. Cappola, Peter Sever, Neil R Poulter, Mark J. Caulfield, Anna F. Dominiczak, Denis C. Shields, Deepak L. Bhatt, Li Zhang, Sean Curtis, John Danesh, Juan P. Casas, Yvonne T. van der Schouw, N. Charlotte Onland‐Moret, Pieter A. Doevendans, Gerald W. Dorn, Martin Farrall, Garret A. FitzGerald, Anders Hamsten, Robert A. Hegele, Aroon D. Hingorani, Marten H. Hofker, Gordon S. Huggins, Thomas Illig, Gail P. Jarvik, Julie A. Johnson, Olaf H. Klungel, William C. Knowler, Wolfgang Köenig, Winfried März, James B. Meigs, Olle Melander, Patricia B. Munroe, Braxton D. Mitchell, Suzette J. Bielinski, Daniel J. Rader, Muredach P. Reilly, Stephen S. Rich, Jerome I. Rotter, Danish Saleheen, Nilesh J. Samani, Eric E. Schadt, Alan R. Shuldiner, Roy L. Silverstein, Kandice Kottke‐Marchant, Philippa J. Talmud, Hugh Watkins, Folkert W. Asselbergs, Paul I. W. de Bakker, Jeanne M. McCaffery, Cisca Wijmenga, Marc S. Sabatine, James G. Wilson, Alex P. Reiner, Donald W. Bowden, Hákon Hákonarson, David S. Siscovick, Brendan J. Keating,

Cancer-related molecular mechanisms research

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10−9) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10−6). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10−7) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10−15). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10−8). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups. To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ∼2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10−9) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10−6). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10−7) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10−15). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10−8). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.