期刊
NATURE GENETICS
卷 52, 期 7, 页码 680-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-0637-y
关键词
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资金
- MVP, Office of Research and Development, Veterans Health Administration [MVP000]
- VA award [I01-BX003362, I01-CX001025, I01CX001737]
- VA Informatics and Computing Infrastructure (VINCI) VA HSR RES [130457]
- National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases [DK101478]
- NIH National Human Genome Research Institute [HG010067]
- Linda Pechenik Montague Investigator award
- VA Cooperative Studies Program
- Veterans Administration [IK2-CX001780]
- National Heart, Lung, and Blood Institute of the NIH [T32 HL007734]
- NIH [UC4-DK-112217, R01 DK087635, R21DK099716, U01 DK091958, U01 DK098246, P30DK111024, R03AI133172]
- Cystic Fibrosis Foundation award [PHILLI12A0]
Genome-wide association meta-analyses among 1.4 million individuals identify 318 new risk loci for type 2 diabetes and provide insight into the contribution of these risk variants to diabetes-related vascular outcomes. 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.
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