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Cell Press, American Journal of Human Genetics, 4(90), p. 753, 2012

DOI: 10.1016/j.ajhg.2012.03.001

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

Journal article published in 2012 by Van Der Schouw Yt, Richa Saxena, Cc Clara C. Elbers, Jm M. Zmuda, Yiran Guo, Berta Almoguera Castillo, Inga Peter, Bruce H R. Wolffenbuttel, Jl L. Mega, Toby Johnson ORCID, Anthonius de Boer, Bf F. Voight, Mark C. H. de Groot, Mb B. Lanktree, Yr R. Li and other authors.
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This paper is available in a repository.

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Abstract

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom approximately 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with approximately 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 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 x 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 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 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 x 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.