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在一项多血统荟萃分析中，对 140 万参与者进行研究，发现了 318 个 2 型糖尿病和相关血管结局的新风险位点。

Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.

机构信息

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.

Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

出版信息

Nat Genet. 2020 Jul;52(7):680-691. doi: 10.1038/s41588-020-0637-y. Epub 2020 Jun 15.

DOI:10.1038/s41588-020-0637-y
PMID:32541925
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7343592/
Abstract

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.

摘要

我们通过百万退伍军人计划（MVP）、DIAMANTE、日本生物银行和其他研究中 228499 例病例和 1178783 例对照的多祖系荟萃分析研究了 2 型糖尿病（T2D）的遗传易感性。我们报告了 568 个关联，包括 286 个常染色体、7 个 X 染色体和 25 个在特定祖先分析中未报告的关联。全转录组关联分析在 687 个新基因中检测到 3568 个与 T2D 相关的基因表达的关联；其中 54 个已知与 FDA 批准的药物相互作用。多基因风险评分（PRS）与 T2D 相关的视网膜病变风险增加强烈相关，与慢性肾病（CKD）、外周动脉疾病（PAD）和神经病变中度相关。我们在 MVP 中研究了 T2D 相关血管结局的遗传病因，并在 13 个变体（包括冠心病（CHD）、CKD、PAD 和神经病变）中观察到 SNP-T2D 相互作用。这些发现可能有助于确定 T2D 的潜在治疗靶点以及将 T2D 与血管结局联系起来的基因组途径。

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