期刊
CIRCULATION RESEARCH
卷 118, 期 1, 页码 83-94出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.115.306629
关键词
coronary artery disease; coronary heart disease; genome-wide association study; genetic pleiotropy; lipids; molecular epidemiology; myocardial infarction; Women's Genome Health Study
资金
- Research Council of Norway [213837, 223273]
- South East Norway Health Authority [2013-123]
- Kristian Gerhard Jebsen Foundation
- National Institutes of Health [R01AG031224, R01EB000790, RC2DA29475]
- European Union
- Leducq Foundation
- CADgenomics
- BMBF
- Forschungskonsortien zur Systemmedizin, e:AtheroSysMED
- DFG [SFB 1123]
- National Heart, Lung, and Blood Institute [HL043851, HL080467, HL099355]
- National Cancer Institute [CA047988]
- Amgen
- National Institute for Health Research [NF-SI-0611-10170] Funding Source: researchfish
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.
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