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

• Type of Material: Article
• Authors: Marijana Vujkovic, Corporal Michael J. Crescenz VA Medical Center; Jacob M. Keaton, Tennessee Valley Healthcare System; Julie A. Lynch, VA Salt Lake City Health Care System; Donald R. Miller, Edith Nourse Rogers Memorial VA Hospital; Jin Zhou, Phoenix VA Health Care System; Catherine Tcheandjieu, VA Palo Alto Health Care System; Jennifer E. Huffman, VA Boston Healthcare System; Themistocles L. Assimes, VA Palo Alto Health Care System; Kim Lorenz, Corporal Michael J. Crescenz VA Medical Center; Xiang Zhu, VA Palo Alto Health Care System; Austin T. Hilliard, VA Palo Alto Health Care System; Renae L. Judy, Corporal Michael J. Crescenz VA Medical Center; Jie Huang, VA Boston Healthcare System; Kyung M. Lee, VA Salt Lake City Health Care System; Derek Klarin, VA Boston Healthcare System; Saiju Pyarajan, VA Boston Healthcare System; John Danesh, University of Cambridge; Olle Melander, Lund University; Asif Rasheed, Center for Non-Communicable Diseases; Nadeem H. Mallick, Punjab Institute of Cardiology; Shahid Hameed, Punjab Institute of Cardiology; Irshad H. Qureshi, King Edward Medical University; Muhammad Naeem Afzal, King Edward Medical University; Uzma Malik, King Edward Medical University; Anjum Jalal, Faisalabad Institute of Cardiology; Shahid Abbas, Faisalabad Institute of Cardiology; Xin Sheng, University of Pennsylvania; Long Gao, University of Pennsylvania; Klaus H. Kaestner, University of Pennsylvania; Katalin Susztak, University of Pennsylvania; Yan Sun, Emory University; Scott L. DuVall, VA Salt Lake City Health Care System; Kelly Cho, VA Boston Healthcare System; Jennifer S. Lee, VA Palo Alto Health Care System; J. Michael Gaziano, VA Boston Healthcare System; Lawrence Phillips, Emory University; James B. Meigs, Broad Institute of MIT and Harvard; Peter D. Reaven, Phoenix VA Health Care System; Peter Wilson, Emory University
• Language: English
• Date: 2020-06-15
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2020
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-020-0637-y
• Title of Journal or Parent Work: NATURE GENETICS
• Volume: 52
• Issue: 7
• Start Page: 680
• End Page: +
• Grant/Funding Information: This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration and was supported by award no. MVP000. This publication does not represent the views of the Department of Veterans Affairs, the US Food and Drug Administration, or the US Government. 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., 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 National Institutes of Health [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.
• Keywords: ENRICHMENT; DISEASE; Life Sciences & Biomedicine; HEALTH; DATABASE; HERITABILITY; GENOME-WIDE; ASSOCIATION; Genetics & Heredity; MUTATIONS; CELL; GENE-EXPRESSION; Science & Technology
• Research Categories: Biology, Cell; Biology, Genetics

Abstract

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.