Discovery and systematic characterization of risk variants and genes for coronary artery disease in over a million participants

被引：350

作者：

Aragam, Krishna G. ^{[1
,2
,3
,4
]}

Jiang, Tao ^{[5
]}

Goel, Anuj ^{[6
,7
]}

Kanoni, Stavroula ^{[8
]}

Wolford, Brooke N. ^{[9
]}

Atri, Deepak S. ^{[3
,10
]}

Weeks, Elle M. ^{[4
]}

Wang, Minxian ^{[3
,4
]}

Hindy, George ^{[11
]}

Zhou, Wei ^{[4
,9
,12
,13
]}

Grace, Christopher ^{[6
,7
]}

Roselli, Carolina ^{[3
]}

Marston, Nicholas A. ^{[14
]}

Kamanu, Frederick K. ^{[14
]}

Surakka, Ida ^{[15
]}

Venegas, Loreto Munoz ^{[16
,17
]}

Sherliker, Paul ^{[18
]}

Koyama, Satoshi ^{[19
]}

Ishigaki, Kazuyoshi ^{[20
]}

Asvold, Bjorn O. ^{[21
,22
,23
]}

Brown, Michael R. ^{[24
]}

Brumpton, Ben ^{[21
,22
]}

de Vries, Paul S. ^{[24
]}

Giannakopoulou, Olga ^{[8
]}

Giardoglou, Panagiota ^{[25
]}

Gudbjartsson, Daniel F. ^{[26
,27
]}

Gueldener, Ulrich ^{[28
]}

Haider, Syed M. Ijlal ^{[16
,17
]}

Helgadottir, Anna ^{[26
]}

Ibrahim, Maysson ^{[29
]}

Kastrati, Adnan ^{[28
,30
]}

Kessler, Thorsten ^{[28
,30
]}

Kyriakou, Theodosios ^{[7
]}

Konopka, Tomasz ^{[8
]}

Li, Ling ^{[28
]}

Ma, Lijiang ^{[31
,32
]}

Meitinger, Thomas ^{[30
,33
,34
]}

Mucha, Soeren ^{[16
,17
]}

Munz, Matthias ^{[16
,17
]}

Murgia, Federico ^{[29
]}

Nielsen, Jonas B. ^{[15
,21
]}

Noethen, Markus M. ^{[35
,36
]}

Pang, Shichao ^{[28
]}

Reinberger, Tobias ^{[16
,17
]}

Schnitzler, Gavin ^{[3
]}

Smedley, Damian ^{[8
]}

Thorleifsson, Gudmar ^{[26
]}

von Scheidt, Moritz ^{[28
,30
]}

Ulirsch, Jacob C. ^{[4
,12
,37
]}

Arnar, David O. ^{[26
,46
,47
]}

机构：

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

[2] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[3] Broad Inst MIT & Harvard, Cardiovasc Dis Initiat, Cambridge, MA 02142 USA

[4] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[5] Univ Cambridge, Dept Publ Hlth & Primary Care, BHF Cardiovasc Epidemiol Unit, Cambridge, England

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

[7] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

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

[9] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI USA

[10] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med & Genet, Boston, MA USA

[11] Qatar Univ, Dept Populat Med, Coll Med, Doha, Qatar

[12] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA

[13] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA

[14] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, TIMI Study Grp, Boston, MA USA

[15] Univ Michigan, Div Cardiol, Dept Internal Med, Ann Arbor, MI USA

[16] Univ Lubeck, Inst Cardiogenet, Lubeck, Germany

[17] Partner Site Hamburg Lubeck Kiel, German Res Ctr Cardiovasc Res DZHK, Lubeck, Germany

[18] Univ Oxford, Med Sci Div, CTSU Nuffield Dept Populat Hlth, Med Res Council Populat Hlth Res Unit, Oxford, England

[19] RIKEN Ctr Integrat Med Sci, Lab Cardiovasc Genom & Informat, Tsurumi Ku, Yokohama, Kanagawa, Japan

[20] RIKEN Ctr Integrat Med Sci, Lab Stat & Translat Genet, Tsurumi Ku, Yokohama, Kanagawa, Japan

[21] Norwegian Univ Sci & Technol, K G Jebsen Ctr Genet Epidemiol, Dept Publ Hlth & Nursing, NTNU, Trondheim, Norway

[22] Norwegian Univ Sci & Technol, HUNT Res Ctr, Levanger, Norway

[23] St Olavs Hosp, Med Clin, Dept Endocrinol, Trondheim, Norway

[24] Univ Texas Hlth Sci Ctr Houston, Human Genet Ctr, Dept Epidemiol Human Genet & Environm Sci, Sch Publ Hlth, Houston, TX USA

[25] Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr Dietet, Athens, Greece

[26] deCODE Genet Amgen Inc, Reykjavik, Iceland

[27] Univ Iceland, Sch Engn & Nat Sci, Reykjavik, Iceland

[28] Tech Univ Munich, Dept Cardiol, German Heart Ctr Munich, Munich, Germany

[29] Univ Oxford, Div Med Sci, CTSU Nuffield Dept Populat Hlth, Oxford, England

[30] Partner Site Munich Heart Alliance, German Res Ctr Cardiovasc Res DZHK, Munich, Germany

[31] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY USA

[32] Icahn Sch Med Mt Sinai, Zena & Michael Wiener Cardiovasc Inst, New York, NY USA

[33] Institute Human Genet, Helmholtz Zentrum Munchen, German Res Ctr Environm Hlth, Neuherberg, Germany

[34] Tech Univ Munich, Inst Human Genet, Klinikum Rechts Isar, Munich, Germany

[35] Univ Bonn, Sch Med, Inst Human Genet, Bonn, Germany

[36] Univ Bonn, Univ Hosp Bonn, Inst Human Genet, Bonn, Germany

[37] Harvard Med Sch, Program Biol & Biomed Sci, Boston, MA USA

[38] Harvard T H Chan Sch Publ Hlth, Boston, MA USA

[39] Univ Tartu, Tartu Univ Hosp, Dept Cardiac Surg, Tartu, Estonia

[40] Univ Tartu, Inst Clin Med, Tartu, Estonia

[41] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY USA

[42] Karolinska Univ, Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden

[43] Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden

[44] Khalifa Univ, Coll Med & Hlth Sci, Abu Dhabi, U Arab Emirates

[45] Univ Tokyo, Dept Cardiovasc Med, Tokyo, Japan

[46] Univ Iceland, Fac Med, Reykjavik, Iceland

[47] Landspitali Natl Univ Hosp Iceland, Div Cardiol, Dept Internal Med, Reykjavik, Iceland

[48] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA

[49] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Tokyo, Japan

[50] Mayo Clin, Dept Cardiovasc Med, Rochester, MN USA

来源：

NATURE GENETICS | 2022年 / 54卷 / 12期

基金：

美国国家科学基金会; 瑞典研究理事会; 英国医学研究理事会; 英国惠康基金; 英国工程与自然科学研究理事会; 美国国家卫生研究院; 欧洲研究理事会; 英国经济与社会研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; LOCI; INHIBITION; IDENTIFICATION; METAANALYSIS; DESIGN;

D O I：

10.1038/s41588-022-01233-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

The discovery of genetic loci associated with complex diseases has outpaced the elucidation of mechanisms of disease pathogenesis. Here we conducted a genome-wide association study (GWAS) for coronary artery disease (CAD) comprising 181,522 cases among 1,165,690 participants of predominantly European ancestry. We detected 241 associations, including 30 new loci. Cross-ancestry meta-analysis with a Japanese GWAS yielded 38 additional new loci. We prioritized likely causal variants using functionally informed fine-mapping, yielding 42 associations with less than five variants in the 95% credible set. Similarity-based clustering suggested roles for early developmental processes, cell cycle signaling and vascular cell migration and proliferation in the pathogenesis of CAD. We prioritized 220 candidate causal genes, combining eight complementary approaches, including 123 supported by three or more approaches. Using CRISPR-Cas9, we experimentally validated the effect of an enhancer in MYO9B, which appears to mediate CAD risk by regulating vascular cell motility. Our analysis identifies and systematically characterizes >250 risk loci for CAD to inform experimental interrogation of putative causal mechanisms for CAD.

引用

页码：1803 / 1815

页数：28

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