TY - JOUR
T1 - Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes with Several Cardiovascular Risk Factors
AU - Leblanc, Marissa
AU - Zuber, Verena
AU - Andreassen, Bettina Kulle
AU - Witoelar, Aree
AU - Zeng, Lingyao
AU - Bettella, Francesco
AU - Wang, Yunpeng
AU - McEvoy, Linda K.
AU - Thompson, Wesley K.
AU - Schork, Andrew J.
AU - Reppe, Sjur
AU - Barrett-Connor, Elizabeth
AU - Ligthart, Symen
AU - Dehghan, Abbas
AU - Gautvik, Kaare M.
AU - Nelson, Christopher P.
AU - Schunkert, Heribert
AU - Samani, Nilesh J.
AU - Ridker, Paul M.
AU - Chasman, Daniel I.
AU - Aukrust, Pål
AU - Djurovic, Srdjan
AU - Frigessi, Arnoldo
AU - Desikan, Rahul S.
AU - Dale, Anders M.
AU - Andreassen, Ole A.
N1 - Publisher Copyright:
© 2016 Nature America, Inc.
PY - 2016/1/8
Y1 - 2016/1/8
N2 - 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.
AB - 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.
KW - Women's Genome Health Study
KW - coronary artery disease
KW - coronary heart disease
KW - genetic pleiotropy
KW - genome-wide association study
KW - lipids
KW - molecular epidemiology
KW - myocardial infarction
UR - http://www.scopus.com/inward/record.url?scp=84954561386&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.115.306629
DO - 10.1161/CIRCRESAHA.115.306629
M3 - Article
C2 - 26487741
AN - SCOPUS:84954561386
SN - 0009-7330
VL - 118
SP - 83
EP - 94
JO - Circulation Research
JF - Circulation Research
IS - 1
ER -
