Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci by Saxena Richa, Elbers Clara C, Guo Yiran, Peter Inga, Gaunt Tom R, Mega Jessica L, Lanktree Matthew B, Tare Archana, Castillo Berta Almoguera, Li Yun R, Johnson Toby, Bruinenberg Marcel, Gilbert-Diamond Diane, Rajagopalan Ramakrishnan, Voight Benjamin F, Balasubramanyam Ashok, Barnard John, Bauer Florianne, Baumert Jens, Bhangale Tushar, Böhm Bernhard O, Braund Peter S, Burton Paul R, Chandrupatla Hareesh R, Clarke Robert, Cooper-DeHoff Rhonda M, Crook Errol D, Davey-Smith George, Day Ian N, de Boer Anthonius, de Groot Mark C H, Drenos Fotios, Ferguson Jane, Fox Caroline S, Furlong Clement E, Gibson Quince, Gieger Christian, Gilhuijs-Pederson Lisa A, Glessner Joseph T, Goel Anuj, Gong Yan, Grant Struan F A, Grobbee Diederick E, Hastie Claire, Humphries Steve E, Kim Cecilia E, Kivimaki Mika, Kleber Marcus, Meisinger Christa, Kumari Meena, Langaee Taimour Y, Lawlor Debbie A, Li Mingyao, Lobmeyer Maximilian T, Maitland-van der Zee Anke-Hilse, Meijs Matthijs F L, Molony Cliona M, Morrow David A, Murugesan Gurunathan, Musani Solomon K, Nelson Christopher P, Newhouse Stephen J, O'Connell Jeffery R, Padmanabhan Sandosh, Palmen Jutta, Patel Sanjey R, Pepine Carl J, Pettinger Mary, Price Thomas S, Rafelt Suzanne, Ranchalis Jane, Rasheed Asif, Rosenthal Elisabeth, Ruczinski Ingo, Shah Sonia, Shen Haiqing, Silbernagel Günther, Smith Erin N, Spijkerman Annemieke W M, Stanton Alice, Steffes Michael W, Thorand Barbara, Trip Mieke, van der Harst Pim, van der A Daphne L, van Iperen Erik P A, van Setten Jessica, van Vliet-Ostaptchouk Jana V, Verweij Niek, Wolffenbuttel Bruce H R, Young Taylor, Zafarmand M Hadi, Zmuda Joseph M, Look AHEAD Research Group, DIAGRAM consortium, Boehnke Michael, Altshuler David, McCarthy Mark, Kao W H Linda, Pankow James S, Cappola Thomas P, Sever Peter, Poulter Neil, Caulfield Mark, Dominiczak Anna, Shields Denis C, Bhatt Deepak L, Zhang Li, Curtis Sean P, Danesh John, Casas Juan P, van der Schouw Yvonne T, Onland-Moret N Charlotte, Doevendans Pieter A, Dorn Gerald W, Farrall Martin, FitzGerald Garret A, Hamsten Anders, Hegele Robert, Hingorani Aroon D, Hofker Marten H, Huggins Gordon S, Illig Thomas, Jarvik Gail P, Johnson Julie A, Klungel Olaf H, Knowler William C, Koenig Wolfgang, März Winfried, Meigs James B, Melander Olle, Munroe Patricia B, Mitchell Braxton D, Bielinski Susan J, Rader Daniel J, Reilly Muredach P, Rich Stephen S, Rotter Jerome I, Saleheen Danish, Samani Nilesh J, Schadt Eric E, Shuldiner Alan R, Silverstein Roy, Kottke-Marchant Kandice, Talmud Philippa J, Watkins Hugh, Asselbergs Folkert W, de Bakker Paul I W, McCaffery Jeanne, Wijmenga Cisca, Sabatine Marc S, Wilson James G, Reiner Alex, Bowden Donald W, Hakonarson Hakon, Siscovick David S, Keating Brendan J in American journal of human genetics (2012). PubMed

Abstract

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.

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