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.
By
Marijana Vujkovic,
Jacob M. Keaton,
Julie A. Lynch,
Donald R. Miller,
Jin Zhou,
Catherine Tcheandjieu,
Jennifer Huffman,
Themistocles L. Assimes,
Renae L Judy,
Jie Huang,
Kyung Min Lee,
Derek Klarin,
Saiju Pyarajan,
John N. Danesh,
Olle Melander,
Asif Rasheed,
Nadeem Qamar,
Saqib S. Sheikh,
Shahid Hameed,
Irshad H. Qureshi,
Muhammad N. Afzal,
Uzma Jahazaib,
Anjum Jalal,
Shahid Abbas,
Xin Sheng,
Long Gao,
Klaus H Kaestner,
Katalin Susztak,
Yan V Sun,
Scott L. Duvall,
Kelly Cho,
Jennifer S. Lee,
John M. Gaziano,
Lawrence S. Philips,
James B Meigs,
Peter D. Reaven,
Peter W. Wilson,
Todd L Edwards,
Daniel J Rader,
Scott M. Damrauer,
Christopher J. O’Donnell,
Philip S. Tsao,
HPAP Consortium, Regeneron Genetics Center, VA Million Veteran Program,
Kyong-Mi Chang,
Benjamin Franklin Voight,
Danish Saleheen
Posted 25 Nov 2019
medRxiv DOI: 10.1101/19012690
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 (MVP) and other biobanks. 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 the risk of T2D-related retinopathy, and additionally 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 the 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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