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

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.

• Authors: 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
• Journal: Circulation research (Circ Res) Vol. 118 Issue 1 Pg. 83-94 (Jan 08 2016) ISSN: 1524-4571 [Electronic] United States
• PMID: 26487741 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Topics

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