A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease

被引：1754

作者：

Nikpay, Majid ^{[1
]}

Goel, Anuj ^{[2
,3
]}

Won, Hong-Hee ^{[4
,5
,6
,7
]}

Hall, Leanne M. ^{[8
]}

Willenborg, Christina ^{[9
,10
]}

Kanoni, Stavroula ^{[11
]}

Saleheen, Danish ^{[12
,13
]}

Kyriakou, Theodosios ^{[2
,3
]}

Nelson, Christopher P. ^{[8
,14
]}

Hopewell, Jemma C. ^{[15
,16
]}

Webb, Thomas R. ^{[8
,14
]}

Zeng, Lingyao ^{[17
,18
]}

Dehghan, Abbas ^{[19
]}

Alver, Maris ^{[20
,21
]}

Armasu, Sebastian M. ^{[22
]}

Auro, Kirsi ^{[23
,24
,25
]}

Bjonnes, Andrew ^{[4
,6
]}

Chasman, Daniel I. ^{[26
,27
]}

Chen, Shufeng ^{[28
,29
]}

Ford, Ian ^{[30
]}

Franceschini, Nora ^{[31
]}

Gieger, Christian ^{[18
,32
,33
]}

Grace, Christopher ^{[2
,3
]}

Gustafsson, Stefan ^{[34
,35
]}

Huang, Jie ^{[36
]}

Hwang, Shih-Jen ^{[37
,38
]}

Kim, Yun Kyoung ^{[39
]}

Kleber, Marcus E. ^{[40
]}

Lau, King Wai ^{[15
,16
]}

Lu, Xiangfeng ^{[28
,29
]}

Lu, Yingchang ^{[41
,42
]}

Lyytikainen, Leo-Pekka ^{[43
,44
]}

Mihailov, Evelin ^{[20
]}

Morrison, Alanna C. ^{[45
]}

Pervjakova, Natalia ^{[20
,23
,24
,25
]}

Qu, Liming ^{[46
]}

Rose, Lynda M. ^{[26
]}

Salfati, Elias ^{[47
]}

Saxena, Richa ^{[4
,6
,48
]}

Scholz, Markus ^{[49
,50
]}

Smith, Albert V. ^{[51
,52
]}

Tikkanen, Emmi ^{[24
,53
]}

Uitterlinden, Andre ^{[19
]}

Yang, Xueli ^{[28
,29
]}

Zhang, Weihua ^{[54
,55
]}

Zhao, Wei ^{[12
]}

de Andrade, Mariza ^{[22
]}

de Vries, Paul S. ^{[19
]}

van Zuydam, Natalie R. ^{[3
,56
]}

Anand, Sonia S. ^{[57
]}

机构：

[1] Univ Ottawa, Inst Heart, Ruddy Canadian Cardiovasc Genet Ctr, Ottawa, ON, Canada

[2] Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England

[3] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[4] Broad Inst MIT & Harvard Univ, Cambridge, MA USA

[5] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[7] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

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

[9] Univ Lubeck, Inst Integrat & Expt Genom, Lubeck, Germany

[10] DZHK German Res Ctr Cardiovasc Res, Lubeck, Germany

[11] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[12] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

[13] Ctr Noncommunicable Dis, Karachi, Pakistan

[14] Glenfield Hosp, NIHR, Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England

[15] Univ Oxford, Nuffield Dept Populat Hlth, Clin Trial Serv Unit, Oxford, England

[16] Univ Oxford, Nuffield Dept Populat Hlth, Epidemiol Studies Unit CTSU, Oxford, England

[17] Tech Univ Munich, Deutsches Herzzentrum Munchen, D-80290 Munich, Germany

[18] DZHK German Ctr Cardiovasc Res, Munich, Germany

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

[20] Univ Tartu, Estonian Genome Ctr, EE-50090 Tartu, Estonia

[21] Univ Tartu, Inst Mol & Cell Biol, EE-50090 Tartu, Estonia

[22] Mayo Clin, Dept Hlth Sci Res, Div Biomed Stat & Informat, Rochester, MN USA

[23] Natl Inst Hlth & Welf, Dept Hlth, Helsinki, Finland

[24] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[25] Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland

[26] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA

[27] Harvard Univ, Sch Med, Boston, MA USA

[28] Chinese Acad Med Sci, Natl Ctr Cardiovasc Dis, Fuwai Hosp, State Key Lab Cardiovasc Dis, Beijing 100730, Peoples R China

[29] Peking Union Med Coll, Beijing 100021, Peoples R China

[30] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland

[31] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA

[32] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany

[33] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Res Unit Mol Epidemiol, Neuherberg, Germany

[34] Uppsala Univ, Dept Med Sci, Mol Epidemiol, Uppsala, Sweden

[35] Uppsala Univ, Sci Life Lab, Uppsala, Sweden

[36] Wellcome Trust Sanger Inst, Hinxton, England

[37] NHLBI, Framingham Heart Study, Framingham, MA USA

[38] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[39] Korea Natl Inst Hlth, Ctr Genome Sci, Chungcheongbuk Do, South Korea

[40] Heidelberg Univ, Med Fac Mannheim, Vth Dept Med Nephrol Hypertensiol Endocrinol Diab, Mannheim, Germany

[41] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[42] Icahn Sch Med Mt Sinai, Genet Obes & Related Metab Traits Program, New York, NY 10029 USA

[43] Fimlab Labs, Dept Clin Chem, Tampere, Finland

[44] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland

[45] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Sch Publ Hlth, Houston, TX 77030 USA

[46] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA

[47] Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA

[48] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA

[49] Univ Leipzig, Fac Med, Inst Med Informat Stat & Epidemiol, D-04109 Leipzig, Germany

[50] LIFE Res Ctr Civilizat Dis, Leipzig, Germany

来源：

NATURE GENETICS | 2015年 / 47卷 / 10期

关键词：

SUSCEPTIBILITY LOCUS; GENE-EXPRESSION; CELL-MIGRATION; HEART-DISEASE; IDENTIFIES; 13; MICE LACKING; VARIANTS; PROTEIN; RISK; ACTIVATION;

D O I：

10.1038/ng.3396

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.

引用

页码：1121 / +

页数：12

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