Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes With Several Cardiovascular Risk Factors

Marissa LeBlanc; Verena Zuber; Bettina Kulle Andreassen; Aree Witoelar; Lingyao Zeng; Francesco Bettella; Yunpeng Wang; Linda K McEvoy; Wesley K Thompson; Andrew J Schork; Sjur Reppe; Elizabeth Barrett-Connor; Symen Ligthart; Abbas Dehghan; Kaare M Gautvik; Christopher P Nelson; Heribert Schunkert; Nilesh J Samani; CARDIoGRAM Consortium; Paul M Ridker; Daniel I Chasman; Pål Aukrust; Srdjan Djurovic; Arnoldo Frigessi; Rahul S Desikan; Anders M Dale; Ole A Andreassen

doi:10.1161/CIRCRESAHA.115.306629

Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes With Several Cardiovascular Risk Factors

Circ Res. 2016 Jan 8;118(1):83-94. doi: 10.1161/CIRCRESAHA.115.306629. Epub 2015 Oct 20.

Authors

Marissa LeBlanc¹, Verena Zuber¹, Bettina Kulle Andreassen¹, Aree Witoelar¹, Lingyao Zeng¹, Francesco Bettella¹, Yunpeng Wang¹, Linda K McEvoy¹, Wesley K Thompson¹, Andrew J Schork¹, Sjur Reppe¹, Elizabeth Barrett-Connor¹, Symen Ligthart¹, Abbas Dehghan¹, Kaare M Gautvik¹, Christopher P Nelson¹, Heribert Schunkert¹, Nilesh J Samani¹; CARDIoGRAM Consortium; Paul M Ridker¹, Daniel I Chasman¹, Pål Aukrust¹, Srdjan Djurovic¹, Arnoldo Frigessi¹, Rahul S Desikan¹, Anders M Dale¹, Ole A Andreassen¹

Affiliation

¹ From the Department of Clinical Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (M.L., B.K.A.); Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, and Research Support Services, Oslo University Hospital, Oslo, Norway (M.L., A.F.); NORMENT - K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway (V.Z., A.W., F.B., Y.W., S.D., O.A.A.); Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway (V.Z., A.W., F.B., S.D., O.A.A.); Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, University of Oslo, Oslo, Norway (B.K.A.); Deutsches Herzzentrum München, Technische Universität München, Munich, Germany (L.Z., H.S.); Deutsches Zentrum für Herz-Kreislauf-Forschung, partner site Munich Heart Alliance, Munich, Germany (L.Z., H.S.); Multimodal Imaging Laboratory, University of California at San Diego, La Jolla (Y.W., L.K.M., A.J.S., R.S.D., A.M.D., O.A.A.); Department of Neurosciences, University of California, San Diego, La Jolla, (Y.W., A.M.D.); Department of Radiology, University of California, San Diego, La Jolla (L.K.M., R.S.D., A.M.D.); Department of Psychiatry, University of California, San Diego, La Jolla (W.K.T., A.M.D.); Cognitive Sciences Graduate Program, University of California, San Diego, La Jolla, (A.J.S.); Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway (S.R.); Department of Medical Biochemistry, Lovisenberg Diakonale Hospital, Oslo, Norway (S.R., K.M.G.); Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (S.R., K.M.G.); Family and Preventive Medicine, Division of Epidemiology, University of California, San Diego, La Jolla (E.B.-C.); Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands (S.L., A.D.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (C.P.N.,

Abstract

Rationale: Coronary artery disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes.

Objective: We aimed to improve discovery of CAD genes and inform the pathogenic relationship between CAD and several cardiovascular disease risk factors using a shared polygenic signal-informed statistical framework.

Methods and results: Using genome-wide association studies summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate methodology, we systematically investigated genetic overlap between CAD and 8 traits related to cardiovascular disease risk factors: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. We found significant enrichment of single-nucleotide polymorphisms associated with CAD as a function of their association with low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. Applying the conditional false discovery rate method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional false discovery rate <0.01). Furthermore, we identified 53 loci with significant effects in both CAD and at least 1 of low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, systolic blood pressure, and type 1 diabetes mellitus.

Conclusions: The observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.

Keywords: Women’s Genome Health Study; coronary artery disease; coronary heart disease; genetic pleiotropy; genome-wide association study; lipids; molecular epidemiology; myocardial infarction.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiovascular Diseases / diagnosis
Cardiovascular Diseases / genetics
Cohort Studies
Coronary Artery Disease / diagnosis
Coronary Artery Disease / genetics*
Female
Genetic Predisposition to Disease / genetics*
Genetic Variation / genetics*
Genome-Wide Association Study / methods*
Humans
Prospective Studies
Risk Factors

Abstract

Publication types

MeSH terms

Grants and funding