Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci
Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci
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DOI：
10.1016/j.ajhg.2011.12.022
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发表时间：
2012-03-09
影响因子：
9.8
通讯作者：
Keating, Brendan J.
中科院分区：
文献类型：
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作者：
Saxena, Richa;Elbers, Clara C.;Keating, Brendan J.
为了确定导致2型糖尿病（T2 D）的遗传因素，我们在39项基于多种族人群的研究、病例对照研究和临床试验中使用定制的类似于50，000个SNP基因分型阵列（ITMAT-Broad-CARe阵列）与类似于2000个候选基因进行了大规模荟萃分析，共计17，418例病例和70，298例对照。首先，对包括14，073例病例和57，489例欧洲血统对照的25项研究的荟萃分析证实了8个具有全基因组意义的T2 D基因座。在独立的全基因组关联研究中发现的推定关联信号的计算机随访分析DIAGRAM联盟进行的一项研究（包括8，130例病例和38，987例对照）确定了一个具有全基因组意义的T2 D基因座（GATAD 2A/CILP 2/PBX 4; p = 5.7 × 10（-9））和两个超过研究范围显著性的位点（SREBF 1和TH/INS; p < 2.4 × 10（-6））。其次，对来自8项非裔美国人研究的1，986例病例和7，695例对照进行的荟萃分析确定了HMGA 2的研究范围内显著性（p = 2.4 x 10（-7））变异和TCF 7 L2的重复变异（p = 5.1 x 10（-15））。第三，条件分析揭示了欧洲血统样本中5个T2 D相关基因和非洲裔美国人样本中HMGA 2内的多个已知和新的独立信号。第四，对所有39项研究进行的多种族荟萃分析确定了BCL 2中T2 D相关变异（p = 2.1 x 10（-8））。最后，来自新的和已建立的T2 D信号的SNP的复合遗传评分与非洲裔美国人、西班牙裔和亚洲人群中糖尿病风险的增加显著相关。总之，涉及密集基因中心方法的大规模荟萃分析发现了导致T2 D风险的其他基因座和变异，并表明多个种族之间T2 D相关信号的大量重叠。
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.