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).
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Data availability
The full summary-level association data from the trans-ancestry meta-analysis for each lipid trait from this report are available through dbGaP, with accession number phs001672.v1.p1.
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Acknowledgements
Data on patients with coronary artery disease and myocardial infarctions have been contributed by the CARDIoGRAMplusC4D investigators and the Myocardial Infarction Genetics and CARDIoGRAM Exome investigators. Both datasets were obtained online (see URLs). This research is based on data from the MVP, Office of Research and Development, Veterans Health Administration, and was supported by the Department of Veterans Affairs Cooperative Studies Program award G002. This research was also supported by three additional Department of Veterans Affairs awards (1I0101BX003340, 1I01BX003362, and 1I01CX001025) and the NIH (T32 HL007734, K01HL125751, R01HL127564). The content of this manuscript does not represent the views of the Department of Veterans Affairs or the United States Government.
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Concept and design: D.K., T.L.A., S.M.D., K.C., K.-M.C., P.S.T., S.K., D.J.R., P.W.F.W., J.C. and J.M.G. Acquisition, analysis or interpretation of data: D.K., S.M.D., Y.V.S., K.C., T.M.T., J.Ho., D.R.G., S.L.D., J.L., G.M.P., M.C., A.M.S., J.Hu., H.T., J.S.L., Y.-L.H., D.J.L., C.A.E., A.H.L., J.A.L., R.C., P.N., D.S., M.V., A.B., S.P., E.D.A., B.M.N., A.N., A.V.K., J.D., K.-M.C., G.A., C.W., F.E.D., J.E.H. and D.J.C. Drafting of the manuscript: D.K. and T.L.A. Critical revision of the manuscript for important intellectual content: S.M.D., Y.V.S., K.C., P.N., C.W., J.A.L., F.E.D., S.L.D., K.-M.C., C.J.O., P.S.T., S.K., D.J.R. and P.W.W. Administrative, technical or material support: D.K., Y.V.S., K.C., J.Ho., D.R.G., S.L.D., J.A.L., Y.H., J.C., J.M.G., C.J.O., P.S.T, J.E.H., and P.W.W.
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S.K. reports grant support from Regeneron and Bayer, grant support and personal fees from Aegerion, personal fees from Regeneron Genetics Center, Merck, Celera, Novartis, Bristol-Myers Squibb, Sanofi, AstraZeneca, Alnylam, Eli Lilly and Leerink Partners, personal fees and other support from Catabasis, and other support from San Therapeutics outside the submitted work. He is also the chair of the scientific advisory board at Genomics Plc. T.M.T., A.H.L., A.B., F.E.D. and D.J.C. are employees of Regeneron Pharmaceuticals. G.A. has received consulting income from Regeneron Genetics Center, 23andMe and Helix. 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 (VA Salt Lake City’s affiliated non-profit): AbbVie Inc., Anolinx LLC, Astellas Pharma Inc., AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim International GmbH, Celgene Corporation, Eli Lilly and Company, Genentech Inc., Genomic Health Inc., Gilead Sciences Inc., GlaxoSmithKline PLC, Innocrin Pharmaceuticals Inc., Janssen Pharmaceuticals Inc., Kantar Health, Myriad Genetic Laboratories Inc., Novartis International AG and PAREXEL International Corporation.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–17 and Supplementary Note
Supplementary Table 9
826 independent genome-wide lipid variants (across 1,014 associations) identified with GCTA-COJO software
Supplementary Table 10
Variance explained for 444 previously mapped independent exome-wide variants, 118 novel loci identified in this study, and 826 independent lipid genome-wide variants identified on conditional analysis in this study
Supplementary Table 11
223 variants (across 223 distinct loci) used for weighted genetic risk score
Supplementary Table 12
Increase in variance explained as a function of the number of repeated measures in MVP non-Hispanic whites (for a fixed sample size of 171,314 MVP participants; only individuals with five or more measures were included)
Supplementary Table 17
Transcriptome-wide association study
Supplementary Table 18
Black-specific novel low-frequency protein-altering variants associated with lipids
Supplementary Table 19
Hispanic-specific novel low-frequency protein-altering variants associated with lipids
Supplementary Table 20
Genome-wide significant pLOF variants for lipids in the MVP discovery analysis
Supplementary Table 21
Exemplar list of 47 rare damaging mutations in PDE3B from Myocardial Infarction Genetics Consortium exome sequencing data used for coronary artery disease analysis
Supplementary Table 22
Statistically significant (P < 4.98 × 10–5) phenome-wide association results for DNA sequence variants within genes targeted by lipid-lowering medicines
Supplementary Table 23
Association of 223-variant lipid genetic risk score with abdominal aortic aneurysm (AAA) risk
Supplementary Table 30
CAD association statistics for 118 novel genome-wide significant loci in the MVP lipids GWAS
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Klarin, D., Damrauer, S.M., Cho, K. et al. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat Genet 50, 1514–1523 (2018). https://doi.org/10.1038/s41588-018-0222-9
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DOI: https://doi.org/10.1038/s41588-018-0222-9
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