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

doi:10.1038/s41588-018-0222-9

. 2018 Nov;50(11):1514-1523.

doi: 10.1038/s41588-018-0222-9. Epub 2018 Oct 1.

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

Derek Klarin^{1

2

3}, Scott M Damrauer^{4

5}, Kelly Cho⁶, Yan V Sun⁷, Tanya M Teslovich⁸, Jacqueline Honerlaw⁶, David R Gagnon^{6

9}, Scott L DuVall^{10

11}, Jin Li^{12

13}, Gina M Peloso⁹, Mark Chaffin², Aeron M Small^{4

14}, Jie Huang⁶, Hua Tang¹⁵, Julie A Lynch^{10

16}, Yuk-Lam Ho⁶, Dajiang J Liu¹⁷, Connor A Emdin^{1

2}, Alexander H Li⁸, Jennifer E Huffman⁶, Jennifer S Lee^{12

13}, Pradeep Natarajan^{1

2

18}, Rajiv Chowdhury¹⁹, Danish Saleheen^{4

20}, Marijana Vujkovic^{4

20}, Aris Baras⁸, Saiju Pyarajan^{6

21}, Emanuele Di Angelantonio¹⁹, Benjamin M Neale^{2

22

23}, Aliya Naheed²⁴, Amit V Khera^{1

2}, John Danesh¹⁹, Kyong-Mi Chang^{4

25}, Gonçalo Abecasis²⁶, Cristen Willer^{27

28

29}, Frederick E Dewey⁸, David J Carey³⁰; Global Lipids Genetics Consortium; Myocardial Infarction Genetics (MIGen) Consortium; Geisinger-Regeneron DiscovEHR Collaboration; VA Million Veteran Program; John Concato^{14

31}, J Michael Gaziano^{6

21

32}, Christopher J O'Donnell^{6

32}, Philip S Tsao^{12

13}, Sekar Kathiresan^{1

2}, Daniel J Rader^{25

32

33

34

35}, Peter W F Wilson^{36

37}, Themistocles L Assimes^{38

39}

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Boston VA Healthcare System, Boston, MA, USA.
⁴ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁵ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
⁷ Department of Epidemiology, Rollins School of Public Health, Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA.
⁸ Regeneron Genetics Center, Tarrytown, NY, USA.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁰ VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
¹¹ Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹² Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁴ Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ University of Massachusetts College of Nursing and Health Sciences, Boston, MA, USA.
¹⁷ Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA.
¹⁸ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁰ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²¹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Initiative for Noncommunicable Diseases, Health Systems and Population Studies Division, International Centre for Diarrheal Disease Research, Dhaka, Bangladesh.
²⁵ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²⁷ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
²⁸ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
²⁹ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
³⁰ Geisinger Health System, Danville, PA, USA.
³¹ Clinical Epidemiology Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
³² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³³ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁴ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁵ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁶ Atlanta VA Medical Center, Decatur, GA, USA.
³⁷ Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
³⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. tassimes@stanford.edu.
³⁹ VA Palo Alto Health Care System, Palo Alto, CA, USA. tassimes@stanford.edu.

PMID: 30275531
PMCID: PMC6521726
DOI: 10.1038/s41588-018-0222-9

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

Derek Klarin et al. Nat Genet. 2018 Nov.

. 2018 Nov;50(11):1514-1523.

doi: 10.1038/s41588-018-0222-9. Epub 2018 Oct 1.

Authors

Affiliations

¹ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Boston VA Healthcare System, Boston, MA, USA.
⁴ Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
⁵ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
⁷ Department of Epidemiology, Rollins School of Public Health, Department of Biomedical Informatics, School of Medicine, Emory University, Atlanta, GA, USA.
⁸ Regeneron Genetics Center, Tarrytown, NY, USA.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
¹⁰ VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
¹¹ Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹² Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ VA Palo Alto Health Care System, Palo Alto, CA, USA.
¹⁴ Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ University of Massachusetts College of Nursing and Health Sciences, Boston, MA, USA.
¹⁷ Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA.
¹⁸ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
²⁰ Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²¹ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
²² Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
²³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Initiative for Noncommunicable Diseases, Health Systems and Population Studies Division, International Centre for Diarrheal Disease Research, Dhaka, Bangladesh.
²⁵ Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
²⁶ Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA.
²⁷ Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA.
²⁸ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
²⁹ Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
³⁰ Geisinger Health System, Danville, PA, USA.
³¹ Clinical Epidemiology Research Center, VA Connecticut Healthcare System, West Haven, CT, USA.
³² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³³ Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁴ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁵ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³⁶ Atlanta VA Medical Center, Decatur, GA, USA.
³⁷ Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
³⁸ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. tassimes@stanford.edu.
³⁹ VA Palo Alto Health Care System, Palo Alto, CA, USA. tassimes@stanford.edu.

PMID: 30275531
PMCID: PMC6521726
DOI: 10.1038/s41588-018-0222-9

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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Figures

**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 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, 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 damaging *PDE3B* 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.**
Forest plot for a representative 33 of the 1004 disorders tested in the *ANGPTL4* 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**
Forest plot for a representative 33 of the 1004 disorders tested in the *PCSK9* 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 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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Comment in

GWAS identifies new blood lipid-associated genetic variants.
Le Bras A. Le Bras A. Nat Rev Cardiol. 2018 Dec;15(12):728. doi: 10.1038/s41569-018-0117-6. Nat Rev Cardiol. 2018. PMID: 30367133 No abstract available.

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References

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[1] Collins R What makes UK Biobank special? The Lancet 379, 1173–1174 (2012). - PubMed

[2] Collins R What makes UK Biobank special? The Lancet 379, 1173–1174 (2012). - PubMed

[3] Gaziano JM et al. Million Veteran Program: A mega-biobank to study genetic influences on health and disease. J Clin Epidemiol 70, 214–23 (2016). - PubMed

[4] Gaziano JM et al. Million Veteran Program: A mega-biobank to study genetic influences on health and disease. J Clin Epidemiol 70, 214–23 (2016). - PubMed

[5] Di Angelantonio E et al. Major lipids, apolipoproteins, and risk of vascular disease. Jama 302, 1993–2000 (2009). - PMC - PubMed

[6] Di Angelantonio E et al. Major lipids, apolipoproteins, and risk of vascular disease. Jama 302, 1993–2000 (2009). - PMC - PubMed

[7] Teslovich TM et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–13 (2010). - PMC - PubMed

[8] Teslovich TM et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707–13 (2010). - PMC - PubMed

[9] Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 45, 1274–83 (2013). - PMC - PubMed

[10] Global Lipids Genetics Consortium et al. Discovery and refinement of loci associated with lipid levels. Nat Genet 45, 1274–83 (2013). - PMC - PubMed

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

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

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