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Saxena, R.* ; Elbers, C.C.* ; Guo, Y.* ; Peter, I.* ; Gaunt, T.R.* ; Mega, J.L.* ; Lanktree, M.B.* ; Tare, A.* ; Castillo, B.A.* ; Li, Y.R.* ; Johnson, T.* ; Bruinenberg, M.* ; Gilbert-Diamond, D.* ; Rajagopalan, R.* ; Voight, B.F.* ; Balasubramanyam, A.* ; Barnard, J.* ; Bauer, F.* ; Baumert, J.J. ; Bhangale, T.* ; Böhm, B.O.* ; Braund, P.S.* ; Burton, P.R.* ; Chandrupatla, H.R.* ; Clarke, R.* ; Cooper-DeHoff, R.M.* ; Crook, E.D.* ; Davey-Smith, G.* ; Day, I.N.* ; de Boer, A.* ; de Groot, M.C.* ; Drenos, F.* ; Ferguson, J.* ; Fox, C.S.* ; Furlong, C.E.* ; Gibson, Q.* ; Gieger, C. ; Gilhuijs-Pederson, L.A.* ; Glessner, J.T.* ; Goel, A.* ; Gong, Y.* ; Grant, S.F.* ; Grobbee, D.E.* ; Hastie, C.* ; Humphries, S.E.* ; Kim, C.E.* ; Kivimaki, M.* ; Kleber, M.* ; Meisinger, C. ; Kumari, M.* ; Langaee, T.Y.* ; Lawlor, D.A.* ; Li, M.* ; Lobmeyer, M.T.* ; Maitland-van der Zee, A.H.* ; Meijs, M.F.* ; Molony, C.M.* ; Morrow, D.A.* ; Murugesan, G.* ; Musani, S.K.* ; Nelson, C.P.* ; Newhouse, S.J.* ; O'Connell, J.R.* ; Padmanabhan, S.* ; Palmen, J.* ; Patel, S.R.* ; Pepine, C.J.* ; Pettinger, M.* ; Price, T.S.* ; Rafelt, S.* ; Ranchalis, J.* ; Rasheed, A.* ; Rosenthal, E.* ; Ruczinski, I.* ; Shah, S.* ; Shen, H.* ; Silbernagel, G.* ; Smith, E.N.* ; Spijkerman, A.W.* ; Stanton, A.* ; Steffes, M.W.* ; Thorand, B. ; Trip, M.* ; van der Harst, P.* ; van der A, D.L.* ; van Iperen, E.P.* ; van Setten, J.* ; van Vliet-Ostaptchouk, J.V.* ; Verweij, N.* ; Wolffenbuttel, B.H.* ; Young, T.* ; Zafarmand, M.H.* ; Zmuda, J.M* ; * ; DIAGRAM Consortium (Gieger, C. ; Huth, C. ; Grallert, H. ; Klopp, N. ; Meitinger, T. ; Petersen, A.-K. ; Thorand, B. ; Illig, T. ; Wichmann, H.-E.) ; Boehnke, M.* ; Altshuler, D.* ; McCarthy, M.* ; Kao, W.H.* ; Pankow, J.S.* ; Cappola, T.P.* ; Sever, P.* ; Poulter, N.* ; Caulfield, M.* ; Dominiczak, A.* ; Shields, D.C.* ; Bhatt, D.L.* ; Zhang, L.* ; Curtis, S.P.* ; Danesh, J.* ; Casas, J.P.* ; van der Schouw, Y.T.* ; Onland-Moret, N.C.* ; Doevendans, P.A.* ; Dorn, G.W.* ; Farrall, M.* ; Fitzgerald, G.A.* ; Hamsten, A.* ; Hegele, R.* ; Hingorani, A.D.* ; Hofker, M.H.* ; Huggins, G.S.* ; Illig, T. ; Jarvik, G.P.* ; Johnson, J.A.* ; Klungel, O.H.* ; Knowler, W.C.* ; Koenig, W.* ; Marz, W.* ; Meigs, J.B.* ; Melander, O.* ; Munroe, P.B.* ; Mitchell, B.D.* ; Bielinski, S.J.* ; Rader, D.J.* ; Reilly, M.P.* ; Rich, S.S.* ; Rotter, J.I.* ; Saleheen, D.* ; Samani, N.J.* ; Schadt, E.E.* ; Shuldiner, A.R.* ; Silverstein, R.* ; Kottke-Marchant, K.* ; Talmud, P.J.* ; Watkins, H.* ; Asselbergs, F.W.* ; de Bakker, P.I.* ; McCaffery, J.* ; Wijmenga, C.* ; Sabatine, M.S.* ; Wilson, J.G.* ; Reiner, A.* ; Bowden, D.W.* ; Hakonarson, H.* ; Siscovick, D.S.* ; Keating, B.J.*

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

Am. J. Hum. Genet. 90, 410-425 (2012)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; INSULIN-RESISTANCE; COMMON VARIANTS; EUROPEAN AMERICANS; AFRICAN-AMERICANS; BLOOD-PRESSURE; RESOURCE CARE; RISK-FACTORS; SNP ARRAY
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