Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.

Richa Saxena; Clara C Elbers; Yiran Guo; Inga Peter; Tom R Gaunt; Jessica L Mega; Matthew B Lanktree; Archana Tare; Berta Almoguera Castillo; Yun R Li; +147 more... Toby Johnson; Marcel Bruinenberg; Diane Gilbert-Diamond; Ramakrishnan Rajagopalan; Benjamin F Voight; Ashok Balasubramanyam; John Barnard; Florianne Bauer; Jens Baumert; Tushar Bhangale; Bernhard O Böhm; Peter S Braund; Paul R Burton; Hareesh R Chandrupatla; Robert Clarke; Rhonda M Cooper-DeHoff; Errol D Crook; George Davey-Smith; Ian N Day; Anthonius de Boer; Mark CH de Groot; Fotios Drenos; Jane Ferguson; Caroline S Fox; Clement E Furlong; Quince Gibson; Christian Gieger; Lisa A Gilhuijs-Pederson; Joseph T Glessner; Anuj Goel; Yan Gong; Struan FA Grant; Diederick E Grobbee; Claire Hastie; Steve E Humphries; Cecilia E Kim; Mika Kivimaki; Marcus Kleber; Christa Meisinger; Meena Kumari; Taimour Y Langaee; Debbie A Lawlor; Mingyao Li; Maximilian T Lobmeyer; Anke-Hilse Maitland-van der Zee; Matthijs FL Meijs; Cliona M Molony; David A Morrow; Gurunathan Murugesan; Solomon K Musani; Christopher P Nelson; Stephen J Newhouse; Jeffery R O'Connell; Sandosh Padmanabhan; Jutta Palmen; Sanjey R Patel; Carl J Pepine; Mary Pettinger; Thomas S Price; Suzanne Rafelt; Jane Ranchalis; Asif Rasheed; Elisabeth Rosenthal; Ingo Ruczinski; Sonia Shah; Haiqing Shen; Günther Silbernagel; Erin N Smith; Annemieke WM Spijkerman; Alice Stanton; Michael W Steffes; Barbara Thorand; Mieke Trip; Pim van der Harst; Daphne L van der A; Erik PA van Iperen; Jessica van Setten; Jana V van Vliet-Ostaptchouk; Niek Verweij; Bruce HR Wolffenbuttel; Taylor Young; M Hadi Zafarmand; Joseph M Zmuda; Look AHEAD Research Group; DIAGRAM consortium; Michael Boehnke; David Altshuler; Mark McCarthy; WH Linda Kao; James S Pankow; Thomas P Cappola; Peter Sever; Neil Poulter; Mark Caulfield; Anna Dominiczak; Denis C Shields; Deepak L Bhatt; Li Zhang; Sean P 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 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 Koenig; Winfried März; James B Meigs; Olle Melander; Patricia B Munroe; Braxton D Mitchell; Susan 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 Silverstein; Kandice Kottke-Marchant; Philippa J Talmud; Hugh Watkins; Folkert W Asselbergs; Paul IW de Bakker; Jeanne McCaffery; Cisca Wijmenga; Marc S Sabatine; James G Wilson; Alex Reiner; Donald W Bowden; Hakon Hakonarson; David S Siscovick; Brendan J Keating; (2012) Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci. American journal of human genetics, 90 (3). pp. 410-425. ISSN 0002-9297 DOI: 10.1016/j.ajhg.2011.12.022

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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.

Item Type	Article
Keywords	genome-wide association, susceptibility loci, insulin-resistance, common, variants, european americans, african-americans, blood-pressure, resource care, risk-factors, snp array
ISI	301762800007