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Discovery of 318 novel loci for type-2 diabetes and related micro- and macrovascular outcomes among 1.4 million participants in a multi-ethnic meta-analysis.

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Vujkovic, Marijana 
Keaton, Jacob M 
Chang, Kyong-Mi 
Voight, Benjamin F 


We investigated type 2 diabetes (T2D) genetic susceptibility in a multi-ethnic meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program, DIAMANTE, Biobank Japan, and other studies. We identified 558 autosomal and 10 X-chromosome T2D-associated variants, of which 286 autosomal and 7 X-chromosome variants were previously unreported. Ancestry-specific analyses identified 25 additional novel T2D-susceptibility variants. Transcriptome-wide association analysis detected 3,568 T2D-associations with T2D-colocalized genetically predicted gene expression of 804 genes in 52 tissues, of which 687 are novel. Fifty-four of these genes are known to interact with FDA-approved drugs and chemical compounds. T2D polygenic risk score was strongly associated with increased risk of T2D-related retinopathy, and showed evidence for association with chronic kidney disease (CKD), neuropathy, and peripheral artery disease (PAD). We investigated the genetic etiology of T2D-related vascular outcomes in MVP and observed statistical SNP-T2D interactions at 13 variants, including 3 for coronary heart disease, 1 for PAD, 2 for stroke, 4 for retinopathy, 2 for CKD, and 1 for neuropathy. Our findings may identify potential novel therapeutic targets for T2D and genomic pathways that link T2D and its vascular outcomes.



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Nature Genetics

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Springer Nature


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This research was also supported by funding from: the Department of Veterans Affairs award I01-BX003362 (P.S.T. and K.M.C) and the VA Informatics and Computing Infrastructure (VINCI) VA HSR RES 130457 (S.L.D) B.F.V. acknowledges support for this work from the NIH/NIDDK (DK101478), the NIH/NHGRI (HG010067) and a Linda Pechenik Montague Investigator award. K.M.C, S.M.D, J.M.G, C.J.O, L.S.P, and P.S.T. are supported by the VA Cooperative Studies Program. S.M.D. is supported by the Veterans Administration [IK2-CX001780]. D.K. is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health [T32 HL007734]. L.S.P. is supported in part by VA awards I01-CX001025, and I01CX001737, NIH awards R21DK099716, U01 DK091958, U01 DK098246, P30DK111024, and R03AI133172, and a Cystic Fibrosis Foundation award PHILLI12A0. We thank all study participants for their contribution. Data on T2D have been contributed by investigators from DIAMANTE Consortium, Biobank Japan, Malmö Diet and Cancer Study, PennCath, MedStar, Pakistan Genomic Resource, Penn Medicine Biobank, and Regeneron Genetics Center. Data on stroke were provided by MEGASTROKE investigators, and data on CKD have been contributed by CKDgen investigators. Data on alpha and beta islet cells have been contributed by the HPAP Consortium. Data on coronary artery disease have been contributed by the CARDIoGRAMplusC4D investigators. We thank dr. Josep Maria Mercader and dr. Aaron Leong for careful review and comments.