TY - JOUR
T1 - 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
AU - The HPAP Consortium
AU - Regeneron Genetics Center
AU - VA Million Veteran Program
AU - Vujkovic, Marijana
AU - Keaton, Jacob M.
AU - Lynch, Julie A.
AU - Miller, Donald R.
AU - Zhou, Jin
AU - Tcheandjieu, Catherine
AU - Huffman, Jennifer E.
AU - Assimes, Themistocles L.
AU - Lorenz, Kimberly
AU - Zhu, Xiang
AU - Hilliard, Austin T.
AU - Judy, Renae L.
AU - Huang, Jie
AU - Lee, Kyung M.
AU - Klarin, Derek
AU - Pyarajan, Saiju
AU - Danesh, John
AU - Melander, Olle
AU - Rasheed, Asif
AU - Mallick, Nadeem H.
AU - Hameed, Shahid
AU - Qureshi, Irshad H.
AU - Afzal, Muhammad Naeem
AU - Malik, Uzma
AU - Jalal, Anjum
AU - Abbas, Shahid
AU - Sheng, Xin
AU - Gao, Long
AU - Kaestner, Klaus H.
AU - Susztak, Katalin
AU - Sun, Yan V.
AU - DuVall, Scott L.
AU - Cho, Kelly
AU - Lee, Jennifer S.
AU - Gaziano, J. Michael
AU - Phillips, Lawrence S.
AU - Meigs, James B.
AU - Reaven, Peter D.
AU - Wilson, Peter W.
AU - Edwards, Todd L.
AU - Rader, Daniel J.
AU - Damrauer, Scott M.
AU - O’Donnell, Christopher J.
AU - Tsao, Philip S.
AU - Atkinson, Mark A.
AU - Powers, Al C.
AU - Naji, Ali
AU - Kaestner, Klaus H.
AU - Abecasis, Goncalo R.
AU - Pyarajan, Saiju
N1 - Publisher Copyright:
© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85087532945&partnerID=8YFLogxK
U2 - 10.1038/s41588-020-0637-y
DO - 10.1038/s41588-020-0637-y
M3 - Article
C2 - 32541925
AN - SCOPUS:85087532945
SN - 1061-4036
VL - 52
SP - 680
EP - 691
JO - Nature Genetics
JF - Nature Genetics
IS - 7
ER -