期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 90, 期 3, 页码 410-425出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2011.12.022
关键词
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资金
- National Heart, Lung, and Blood Institute
- NIDDK NIH [DK089378]
- Netherlands Organization for Scientific Research (NWO)
- Massachusetts Institute of Technology [N01-HC-65226]
- British Heart Foundation [PG/09/022/26739, RG/08/008/25291, RG/07/008/23674, RG/08/014/24067, RG/10/12/28456] Funding Source: researchfish
- Medical Research Council [G0100222, G9521010, G9817803B, G8802774, G0902037, MC_U137686857, G19/35, G0600705] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10116] Funding Source: researchfish
- MRC [MC_U137686857, G0902037, G0600705, G9521010] Funding Source: UKRI
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 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.
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