Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.
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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 ∼50,000 SNP genotyping array (the ITMAT-Ó³»´«Ã½-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. |
| Year of Publication | 2012
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| Journal | Am J Hum Genet
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| Volume | 90
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| Issue | 3
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| Pages | 410-25
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| Date Published | 2012 Mar 09
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| ISSN | 1537-6605
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| URL | |
| DOI | 10.1016/j.ajhg.2011.12.022
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| PubMed ID | 22325160
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| PubMed Central ID | PMC3309185
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| Grant list | G9521010 / Medical Research Council / United Kingdom
PG/09/022/26739 / British Heart Foundation / United Kingdom
RG/08/008/25291 / British Heart Foundation / United Kingdom
G0600705 / Medical Research Council / United Kingdom
G19/35 / Medical Research Council / United Kingdom
G0100222 / Medical Research Council / United Kingdom
U01 GM074492 / GM / NIGMS NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
G8802774 / Medical Research Council / United Kingdom
G0902037 / Medical Research Council / United Kingdom
UL1 TR000124 / TR / NCATS NIH HHS / United States
MC_U137686857 / Medical Research Council / United Kingdom
R01 HL074730 / HL / NHLBI NIH HHS / United States
K24 DK080140 / DK / NIDDK NIH HHS / United States
090532 / Wellcome Trust / United Kingdom
N01HC65226 / HL / NHLBI NIH HHS / United States
R01 HL088577 / HL / NHLBI NIH HHS / United States
R21 DK089378 / DK / NIDDK NIH HHS / United States
RG/08/014/24067 / British Heart Foundation / United Kingdom
P30 DK017047 / DK / NIDDK NIH HHS / United States
N01-HC-65226 / HC / NHLBI NIH HHS / United States
RG/07/008/23674 / British Heart Foundation / United Kingdom
RG/10/12/28456 / British Heart Foundation / United Kingdom
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