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 - Funding Information:
None of the sponsors of the following authors had a role in the design and conduct of the study, in the collection, management, analysis and interpretation of the data, or in the preparation, review or approval of the manuscript. D.S. has received support from the British Heart Foundation, Pfizer, Regeneron, Genentech and Eli Lilly pharmaceuticals. L.S.P. has served on Scientific Advisory Boards for Janssen, and received research support from Abbvie, Merck, Amylin, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, Abbvie, Vascular Pharmaceuticals, Janssen, Glaxo SmithKline, Pfizer, Kowa and the Cystic Fibrosis Foundation. L.S.P. is a cofounder, officer, board member and stockholder of the diabetes management-related software company Diasyst. S.L.D. has received research grant support from the following for-profit companies through the University of Utah or the Western Institute for Biomedical Research (an affiliated non-profit of VA Salt Lake City Health Care System): AbbVie, Anolinx, Astellas Pharma, AstraZeneca Pharmaceuticals, Boehringer Ingelheim International, Celgene Corporation, Eli Lilly and Company, Genentech, Genomic Health, Gilead Sciences, GlaxoSmithKline, Innocrin Pharmaceuticals, Janssen Pharmaceuticals, Kantar Health, Myriad Genetic Laboratories, Novartis International and PAREXEL International Corporation. P.D.R. has received research grant support from the following for-profit companies: Bristol Myers Squib and Lysulin, and has consulted with Intercept Pharmaceuticals and Boston Heart Diagnostics. S.M.D. receives research support to the University of Pennsylvania from RenalytixAI and consults for Calico Labs.
Funding Information:
This publication does not represent the views of the VA, the US Food and Drug Administration, or the US Government. This research was also supported by funding from: the VA 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 National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (DK101478), the NIH National Human Genome Research Institute (HG010067) and a Linda Pechenik Montague Investigator award. K.-M.C., S.M.D., J.M.G., C.J.O., L.S.P., J.S.L., 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 NIH (T32 HL007734). K.H.K. is supported by NIH award UC4-DK-112217. K.S. is supported by NIH R01 DK087635. 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 were contributed by investigators from the 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 were contributed by CKDgen investigators. Data on islet α-and β-cells were contributed by the HPAP Consortium (RRID:SCR_016202 and https://hpap.pmacs.upenn.edu/). Data on coronary artery disease were contributed by the CARDIoGRAMplusC4D investigators. We thank Josep Maria Mercader and Aaron Leong for careful review and comments.
Funding Information:
This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration and was supported by award no. MVP000.
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 -