Nikpay Majid, Goel Anuj, Won Hong-Hee, Hall Leanne M, Willenborg Christina, Kanoni Stavroula, Saleheen Danish, Kyriakou Theodosios, Nelson Christopher P, Hopewell Jemma C, Webb Thomas R, Zeng Lingyao, Dehghan Abbas, Alver Maris, Armasu Sebastian M, Auro Kirsi, Bjonnes Andrew, Chasman Daniel I, Chen Shufeng, Ford Ian, Franceschini Nora, Gieger Christian, Grace Christopher, Gustafsson Stefan, Huang Jie, Hwang Shih-Jen, Kim Yun Kyoung, Kleber Marcus E, Lau King Wai, Lu Xiangfeng, Lu Yingchang, Lyytikäinen Leo-Pekka, Mihailov Evelin, Morrison Alanna C, Pervjakova Natalia, Qu Liming, Rose Lynda M, Salfati Elias, Saxena Richa, Scholz Markus, Smith Albert V, Tikkanen Emmi, Uitterlinden Andre, Yang Xueli, Zhang Weihua, Zhao Wei, de Andrade Mariza, de Vries Paul S, van Zuydam Natalie R, Anand Sonia S, Bertram Lars, Beutner Frank, Dedoussis George, Frossard Philippe, Gauguier Dominique, Goodall Alison H, Gottesman Omri, Haber Marc, Han Bok-Ghee, Huang Jianfeng, Jalilzadeh Shapour, Kessler Thorsten, König Inke R, Lannfelt Lars, Lieb Wolfgang, Lind Lars, Lindgren Cecilia M, Lokki Marja-Liisa, Magnusson Patrik K, Mallick Nadeem H, Mehra Narinder, Meitinger Thomas, Memon Fazal-Ur-Rehman, Morris Andrew P, Nieminen Markku S, Pedersen Nancy L, Peters Annette, Rallidis Loukianos S, Rasheed Asif, Samuel Maria, Shah Svati H, Sinisalo Juha, Stirrups Kathleen E, Trompet Stella, Wang Laiyuan, Zaman Khan S, Ardissino Diego, Boerwinkle Eric, Borecki Ingrid B, Bottinger Erwin P, Buring Julie E, Chambers John C, Collins Rory, Cupples L Adrienne, Danesh John, Demuth Ilja, Elosua Roberto, Epstein Stephen E, Esko Tõnu, Feitosa Mary F, Franco Oscar H, Franzosi Maria Grazia, Granger Christopher B, Gu Dongfeng, Gudnason Vilmundur, Hall Alistair S, Hamsten Anders, Harris Tamara B, Hazen Stanley L, Hengstenberg Christian, Hofman Albert, Ingelsson Erik, Iribarren Carlos, Jukema J Wouter, Karhunen Pekka J, Kim Bong-Jo, Kooner Jaspal S, Kullo Iftikhar J, Lehtimäki Terho, Loos Ruth J F, Melander Olle, Metspalu Andres, März Winfried, Palmer Colin N, Perola Markus, Quertermous Thomas, Rader Daniel J, Ridker Paul M, Ripatti Samuli, Roberts Robert, Salomaa Veikko, Sanghera Dharambir K, Schwartz Stephen M, Seedorf Udo, Stewart Alexandre F, Stott David J, Thiery Joachim, Zalloua Pierre A, O'Donnell Christopher J, Reilly Muredach P, Assimes Themistocles L, Thompson John R, Erdmann Jeanette, Clarke Robert, Watkins Hugh, Kathiresan Sekar, McPherson Ruth, Deloukas Panos, Schunkert Heribert, Samani Nilesh J, Farrall Martin
Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Nat Genet. 2015 Oct;47(10):1121-1130. doi: 10.1038/ng.3396. Epub 2015 Sep 7.
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 ∼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.
目前关于影响冠状动脉疾病（CAD）风险的基因变异的认识，很大程度上基于对常见单核苷酸多态性（SNP）的全基因组关联研究（GWAS）分析。利用来自千人基因组计划的分型单倍型，我们报告了一项对约18.5万例CAD病例和对照的GWAS荟萃分析，检测了670万个常见变异（次要等位基因频率（MAF）>0.05）和270万个低频变异（0.005<MAF<0.05）。除了确认大多数已知的CAD相关位点外，我们还鉴定出了10个新位点（8个加性和2个隐性），这些位点包含新涉及血管壁生物学过程的候选因果基因。我们观察到基因座内等位基因异质性，但几乎没有证据表明低频变异具有更大效应，也没有合成关联的证据。我们的分析对CAD的精细遗传结构进行了全面调查，表明对这种常见疾病的遗传易感性很大程度上由效应大小较小的常见SNP决定。
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