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.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Vujkovic, M; Keaton, JM; Lynch, JA; Miller, DR; Zhou, J; Tcheandjieu, C; Huffman, JE; Assimes, TL; Lorenz, K; Zhu, X; Hilliard, AT; Judy, RL; Huang, J; Lee, KM; Klarin, D; Pyarajan, S; Danesh, J; Melander, O; Rasheed, A; Mallick, NH; Hameed, S; Qureshi, IH; Afzal, MN; Malik, U; Jalal, A; Abbas, S; Sheng, X; Gao, L; Kaestner, KH; Susztak, K; Sun, YV; DuVall, SL; Cho, K; Lee, JS; Gaziano, JM; Phillips, LS; Meigs, JB; Reaven, PD; Wilson, PW; Edwards, TL; Rader, DJ; Damrauer, SM; O'Donnell, CJ; Tsao, PS; HPAP Consortium, ; Regeneron Genetics Center, ; VA Million Veteran Program, ; Chang, K-M; Voight, BF; Saleheen, D

Published Date

  • July 2020

Published In

Volume / Issue

  • 52 / 7

Start / End Page

  • 680 - 691

PubMed ID

  • 32541925

Pubmed Central ID

  • PMC7343592

Electronic International Standard Serial Number (EISSN)

  • 1546-1718

Digital Object Identifier (DOI)

  • 10.1038/s41588-020-0637-y

Language

  • eng

Conference Location

  • United States