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

被引：52

作者：

LeBlanc, Marissa ^{[1
,2
,3
]}

Zuber, Verena ^{[4
,5
]}

Andreassen, Bettina Kulle ^{[1
,2
]}

Witoelar, Aree ^{[4
,5
]}

Zeng, Lingyao ^{[6
]}

Bettella, Francesco ^{[4
,5
]}

Wang, Yunpeng ^{[4
,7
,8
]}

McEvoy, Linda K. ^{[7
,9
]}

Thompson, Wesley K. ^{[10
]}

Schork, Andrew J. ^{[7
,11
]}

Reppe, Sjur ^{[12
,13
,14
]}

Barrett-Connor, Elizabeth ^{[15
]}

Ligthart, Symen ^{[16
]}

Dehghan, Abbas ^{[16
]}

Gautvik, Kaare M. ^{[13
,14
]}

Nelson, Christopher P. ^{[17
,18
]}

Schunkert, Heribert ^{[6
]}

Samani, Nilesh J. ^{[17
,18
]}

Ridker, Paul M. ^{[19
]}

Chasman, Daniel I. ^{[19
]}

Aukrust, Pal ^{[20
,21
,22
,23
]}

Djurovic, Srdjan ^{[4
,5
]}

Frigessi, Arnoldo ^{[2
,3
]}

Desikan, Rahul S. ^{[7
,9
,24
]}

Dale, Anders M. ^{[7
,8
,9
,10
]}

Andreassen, Ole A. ^{[4
,5
,7
]}

机构：

[1] Univ Oslo, Dept Clin Mol Biol, Inst Clin Med, Oslo, Norway

[2] Univ Oslo, Oslo Ctr Biostat & Epidemiol, Dept Biostat, Oslo, Norway

[3] Oslo Univ Hosp, Res Support Serv, N-0424 Oslo, Norway

[4] Univ Oslo, NORMENT KG Jebsen Ctr Psychosis Res, Inst Clin Med, Oslo, Norway

[5] Oslo Univ Hosp, Div Mental Hlth & Addict, N-0424 Oslo, Norway

[6] Tech Univ Munich, Deutsch Herzzentrum Munchen, D-80290 Munich, Germany

[7] Univ Calif San Diego, Multimodal Imaging Lab, La Jolla, CA 92093 USA

[8] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[9] Univ Calif San Diego, Dept Radiol, San Diego, CA 92103 USA

[10] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA

[11] Univ Calif San Diego, Cognit Sci Grad Program, San Diego, CA 92103 USA

[12] Oslo Univ Hosp, Dept Med Biochem, N-0424 Oslo, Norway

[13] Lovisenberg Diakonale Hosp, Dept Med Biochem, Oslo, Norway

[14] Univ Oslo, Inst Basic Med Sci, Oslo, Norway

[15] Univ Calif San Diego, Family & Prevent Med, Div Epidemiol, La Jolla, CA 92093 USA

[16] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[17] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England

[18] Glenfield Hosp, Natl Inst Hlth Res, Leicester Cardiovasc Dis Biomed Res Unit, Leicester, Leics, England

[19] Brigham & Womens Hosp, Div Preventat Med, Ctr Cardiovasc Dis Prevent, Boston, MA 02115 USA

[20] Oslo Univ Hosp, Internal Med Res Inst, N-0424 Oslo, Norway

[21] Oslo Univ Hosp, Sect Clin Immunol & Infect Dis, N-0424 Oslo, Norway

[22] Univ Oslo, Oslo, Norway

[23] Univ Oslo, KG Jebsen Inflammatory Res Ctr, Oslo, Norway

[24] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, Neuroradiol Sect, San Francisco, CA 94143 USA

来源：

CIRCULATION RESEARCH | 2016年 / 118卷 / 01期

基金：

美国国家卫生研究院;

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; GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; HEART-DISEASE; BLOOD-PRESSURE; COMMON VARIANTS; METABOLIC SYNDROME; ESSENTIAL-HYPERTENSION; LEVERAGING PLEIOTROPY; MISSING HERITABILITY; LOCI;

D O I：

10.1161/CIRCRESAHA.115.306629

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：83 / 94

页数：12

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