Genetics of blood lipids among similar to 300,000 multi-ethnic participants of the Million Veteran Program

• Type of Material: Article
• Authors: Derek Klarin, Harvard Medical School; Scott M. Damrauer, Corporal Michael Crescenz VA Medical Center; Kelly Cho, Boston VA Healthcare System; Yan Sun, Emory University; Tanya M. Teslovich, Regeneron Genetics Center; Jacqueline Honerlaw, Boston VA Healthcare System; David R Gagnon, Boston VA Healthcare System; Scott L. Du Vall, VA Salt Lake City Health Care System; Jin Li, Stanford University; Gina M. Peloso, Boston University; Mark Chaffin, Broad Institute of MIT & Harvard; Aeron M. Small, Corporal Michael Crescenz VA Medical Center; Jie Huang, Boston VA Healthcare System; Hua Tang, Stanford University; Julie A. Lynch, VA Salt Lake City Health Care System; Yuk-Lam Ho, Boston VA Healthcare System; Dajiang J. Liu, Penn State College of Medicine; Connor A. Emdin, Harvard Medical School; Alexander H. Li, Regeneron Genetics Center; Peter Wilson, Emory University
• Language: English
• Date: 2018-11-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-018-0222-9
• Title of Journal or Parent Work: Nature Genetics
• ISSN: 1061-4036
• Volume: 50
• Issue: 11
• Start Page: 1514
• End Page: +
• Grant/Funding Information: This research was also supported by three additional Department of Veterans Affairs awards (I01-01BX03340, I01-BX002641, and I01-CX001025); and the NIH (T32 HL007734, K01HL125751, R01HL127564).; This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration; and was supported by the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) award #G002.
• Keywords: Genetics & Heredity; RISK; LOCI; Life Sciences & Biomedicine; LOW-FREQUENCY; HEART-DISEASE; CODING VARIANTS; METAANALYSIS; MUTATIONS; CORONARY-ARTERY-DISEASE; Science & Technology; BIOBANK; GENOME-WIDE ASSOCIATION
• Research Categories: Health Sciences, Medicine and Surgery; Biology, Genetics

Abstract

The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n > 600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).