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

Derek Klarin, Scott M Damrauer, Kelly Cho, Yan V Sun, Tanya M Teslovich, Jacqueline Honerlaw, David R Gagnon, Scott L DuVall, Jin Li, Gina M Peloso, Mark Chaffin, Aeron M Small, Jie Huang, Hua Tang, Julie A Lynch, Yuk-Lam Ho, Dajiang J Liu, Connor A Emdin, Alexander H Li, Jennifer E Huffman, Jennifer S Lee, Pradeep Natarajan, Rajiv Chowdhury, Danish Saleheen, Marijana Vujkovic, Aris Baras, Saiju Pyarajan, Emanuele Di Angelantonio, Benjamin M Neale, Aliya Naheed, Amit V Khera, John Danesh, Kyong-Mi Chang, Gonçalo Abecasis, Cristen Willer, Frederick E Dewey, David J Carey, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, John Concato, J Michael Gaziano, Christopher J O'Donnell, Philip S Tsao, Sekar Kathiresan, Daniel J Rader, Peter W F Wilson, Themistocles L Assimes, Derek Klarin, Scott M Damrauer, Kelly Cho, Yan V Sun, Tanya M Teslovich, Jacqueline Honerlaw, David R Gagnon, Scott L DuVall, Jin Li, Gina M Peloso, Mark Chaffin, Aeron M Small, Jie Huang, Hua Tang, Julie A Lynch, Yuk-Lam Ho, Dajiang J Liu, Connor A Emdin, Alexander H Li, Jennifer E Huffman, Jennifer S Lee, Pradeep Natarajan, Rajiv Chowdhury, Danish Saleheen, Marijana Vujkovic, Aris Baras, Saiju Pyarajan, Emanuele Di Angelantonio, Benjamin M Neale, Aliya Naheed, Amit V Khera, John Danesh, Kyong-Mi Chang, Gonçalo Abecasis, Cristen Willer, Frederick E Dewey, David J Carey, Global Lipids Genetics Consortium, Myocardial Infarction Genetics (MIGen) Consortium, Geisinger-Regeneron DiscovEHR Collaboration, VA Million Veteran Program, John Concato, J Michael Gaziano, Christopher J O'Donnell, Philip S Tsao, Sekar Kathiresan, Daniel J Rader, Peter W F Wilson, Themistocles L Assimes

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).

Figures

Figure 1.. GWAS Study Design
Figure 1.. GWAS Study Design
a) DNA sequence variants across 3 separate ancestry groups in the Million Veteran Program were meta-analyzed using an inverse-variance weighted fixed effects method in the discovery phase (Stage 1). Variants with suggestive association were then brought forward for independent replication. b) DNA sequence variants with suggestive association (two-sided linear regression P < 10−4) in discovery (Stage 1) were brought forward for independent replication and tested using summary statistics from the 2017 exome-array focused GLGC meta-analysis (Stage 2a). Only variants with suggestive association in Stage 1 that were not present in the GLGC 2017 exome-array study (Stage 2a) were alternatively replicated in the 2013 GLGC “joint meta-analysis” (Stage 2b). Abbreviations: MVP, Million Veteran Program; GWAS, genome-wide association study; EHR, electronic health record; GLGC, Global Lipids Genetics Consortium
Figure 2.. Comparison of 354 Independent Lipid…
Figure 2.. Comparison of 354 Independent Lipid Associated Variants Across Ethnicities
Allele frequencies observed in white individuals (n=215,196; x-axes) compared to black (a, n=57,280; R = 0.72,) or Hispanic(b, n=24,742; R = 0.96) individuals for lipid-associated variants are shown. Effect estimates for LDL-C association in white individuals (n = 215,196; x-axes) compared to black (c, n = 57,280; β = 1.07) or Hispanic (d, n = 24,742; β = 1.06) individuals are also depicted. Abbreviations: SD, Standard Deviations; LDL-C, Low-Density Lipoprotein Cholesterol; R = Pearson correlation coefficient
Figure 3.. PDE3B Loss of Gene Function,…
Figure 3.. PDE3B Loss of Gene Function, Lipids, and Coronary Disease
Linear regression results for the association of the predicted loss of function mutation p.Arg783Ter in PDE3B with HDL-C(a) and triglycerides (b) for white veterans in MVP with independent replication in the DiscovEHR study. Two-sided P values are displayed. c) Meta-analysis of the association of damagingPDE3B mutations and coronary artery disease across five studies, including three (MIGen, PMBB, DiscovEHR) with exome sequencing. Logistic regression results were pooled in an inverse-variance weighted fixed effects meta-analysis. Minimal evidence of heterogeneity across cohorts was observed (I = 0%). Two-sided P values are displayed. Abbreviations: MVP, Million Veteran Program; HDL-C, High-Density Lipoprotein Cholesterol; TG, Triglycerides; UKBB, UK Biobank; MIGen, Myocardial Infarction Genetics Consortium; PMBB, Penn Medicine Biobank
Figure 4.. ANGPTL4 40Lys Carrier Disease Associations.
Figure 4.. ANGPTL4 40Lys Carrier Disease Associations.
Forest plot for a representative 33 of the 1004 disorders tested in theANGPTL4 p.Glu40Lys PheWAS. Statistically significant logistic regression associations are shown in blue. Two-sided P values are displayed.
Figure 5.. PCSK9 46Leu Carrier Disease Associations
Figure 5.. PCSK9 46Leu Carrier Disease Associations
Forest plot for a representative 33 of the 1004 disorders tested in thePCSK9 p.Arg46Leu PheWAS. Statistically significant logistic regression associations are shown in blue. Two-sided P values are displayed.
Figure 6.. Lipid Associations with Abdominal Aortic…
Figure 6.. Lipid Associations with Abdominal Aortic Aneurysm
Logistic regression association results of the 223 variant lipid genetic risk score with abdominal aortic aneurysm in a multivariable Mendelian randomization analysis. Odds ratios are displayed per 1-standard deviation genetically increased lipid fraction. Two-sided P values are displayed. Abbreviations: HDL, High-Density Lipoprotein; LDL, Low-Density Lipoprotein

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Source: PubMed

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