Large-scale genome-wide association study of coronary artery disease in genetically diverse populations

被引：193

作者：

Tcheandjieu, Catherine ^{[1
,2
,3
,4
]}

Zhu, Xiang ^{[1
,5
,6
,7
]}

Hilliard, Austin T. ^{[1
]}

Clarke, Shoa L. ^{[1
,2
]}

Napolioni, Valerio ^{[8
,9
]}

Ma, Shining ^{[5
]}

Lee, Kyung Min ^{[10
]}

Fang, Huaying ^{[11
]}

Chen, Fei ^{[12
]}

Lu, Yingchang ^{[13
]}

Tsao, Noah L. ^{[14
]}

Raghavan, Sridharan ^{[15
,16
]}

Koyama, Satoshi ^{[17
]}

Gorman, Bryan R. ^{[18
,19
]}

Vujkovic, Marijana ^{[20
,21
]}

Klarin, Derek ^{[1
,18
,22
,23
,24
,25
]}

Levin, Michael G. ^{[20
,21
]}

Sinnott-Armstrong, Nasa ^{[1
,11
]}

Wojcik, Genevieve L. ^{[26
]}

Plomondon, Mary E. ^{[27
,28
]}

Maddox, Thomas M. ^{[29
,30
]}

Waldo, Stephen W. ^{[27
,28
,31
]}

Bick, Alexander G. ^{[32
]}

Pyarajan, Saiju ^{[18
,33
]}

Huang, Jie ^{[18
,34
,35
]}

Song, Rebecca ^{[18
]}

Ho, Yuk-Lam ^{[18
]}

Buyske, Steven ^{[36
]}

Kooperberg, Charles ^{[37
]}

Haessler, Jeffrey ^{[37
]}

Loos, Ruth J. F. ^{[38
]}

Do, Ron ^{[38
,39
]}

Verbanck, Marie ^{[38
,39
,40
]}

Chaudhary, Kumardeep ^{[38
,39
]}

North, Kari E. ^{[41
]}

Avery, Christy L. ^{[41
]}

Graff, Mariaelisa ^{[41
]}

Haiman, Christopher A. ^{[12
]}

Le Marchand, Loic ^{[42
]}

Wilkens, Lynne R. ^{[42
]}

Bis, Joshua C. ^{[43
]}

Leonard, Hampton ^{[44
,45
]}

Shen, Botong ^{[46
]}

Lange, Leslie A. ^{[47
,48
,49
]}

Giri, Ayush ^{[50
,51
]}

Dikilitas, Ozan ^{[52
]}

Kullo, Iftikhar J. ^{[52
]}

Stanaway, Ian B. ^{[53
]}

Jarvik, Gail P. ^{[54
,55
]}

Gordon, Adam S. ^{[56
]}

机构：

[1] VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA

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

[3] Gladstone Inst, Gladstone Inst Data Sci & Biotechnol, San Francisco, CA 94158 USA

[4] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[5] Stanford Univ, Dept Stat, Stanford, CA 94305 USA

[6] Penn State Univ, Dept Stat, University Pk, PA 16802 USA

[7] Penn State Univ, Huck Inst Life Sci, University Pk, PA 16802 USA

[8] Univ Camerino, Sch Biosci & Vet Med, Camerino, Italy

[9] Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, Stanford, CA 94305 USA

[10] VA Salt Lake City Hlth Care Syst, VA Informat & Comp Infrastruct, Salt Lake City, UT USA

[11] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA

[12] Univ Southern Calif, Ctr Genet Epidemiol, Dept Prevent Med, Los Angeles, CA USA

[13] Vanderbilt Univ Sch Med, Vanderbilt Genet Inst, Nashville, TN USA

[14] Univ Penn, Dept Surg, Perelman Sch Med, Philadelphia, PA 19104 USA

[15] VA Eastern Colorado Hlth Care Syst, Med Serv, Aurora, CO USA

[16] Univ Colorado, Dept Med, Anschutz Med Campus, Aurora, CO USA

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

[18] VA Boston Healthcare Syst, Boston, MA USA

[19] Booz Allen Hamilton, Mclean, VA USA

[20] Corporal Michael J Crescenz VA Med Ctr, Philadelphia, PA USA

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

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

[23] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[24] Univ Florida, Sch Med, Div Vasc Surg & Endovasc Therapy, Gainesville, FL USA

[25] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[26] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA

[27] Rocky Mt Reg VA Med Ctr, Dept Med, Aurora, CO USA

[28] VHA Off Qual & Patient Safety, CART Program, Washington, DC USA

[29] JC HealthCare Washington Univ Sch Med, Healthcare Innovat Lab, St Louis, MO USA

[30] Washington Univ, Sch Med, Div Cardiol, St Louis, MO USA

[31] Univ Colorado, Div Cardiol, Sch Med, Aurora, CO USA

[32] Vanderbilt Univ Sch Med, Dept Biomed Informat, Div Genet Med, Nashville, TN USA

[33] Harvard Med Sch, Brigham Womens Hosp, Dept Med, Boston, MA 02115 USA

[34] Peking Univ, Dept Global Hlth, Sch Publ Hlth, Beijing, Peoples R China

[35] Southern Univ Sci & Technol, Sch Publ Hlth & Emergency Management, Shenzhen, Peoples R China

[36] Rutgers State Univ, Dept Stat, Piscataway, NJ USA

[37] Fred Hutchinson Canc Ctr, Div Publ Hlth Sci, Seattle, WA USA

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

[39] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[40] Univ Paris, EA 7537 BioSTM, Paris, France

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

[42] Univ Hawaii, Univ Hawaii Canc Ctr, Canc Epidemiol Program, Honolulu, HI USA

[43] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[44] NIA, Mol Genet Sect, Lab Neurogenet, Bethesda, MD 20892 USA

[45] Data Tecn Intl LLC, Glen Echo, MD USA

[46] NIA, Hlth Dispar Res Sect, NIH, Baltimore, MD 21224 USA

[47] Dept Med, Div Biomed Informat & Personalized Med, Aurora, CO USA

[48] Lifecourse Epidemiol Adipos & Diabet LEAD Ctr, Aurora, CO USA

[49] Univ Colorado, Dept Epidemiol, Colorado Sch Publ Hlth, Anschutz Med Campus, Aurora, CO USA

[50] Vanderbilt Univ Sch Med, Dept Med, Div Epidemiol, Nashville, TN USA

来源：

NATURE MEDICINE | 2022年 / 28卷 / 08期

基金：

美国国家卫生研究院;

关键词：

POLYGENIC RISK SCORES; SUSCEPTIBILITY LOCI; CLINICAL-ASSESSMENT; HEART-DISEASE; DATA QUALITY; HEALTH; HERITABILITY; METAANALYSIS; REGRESSION; PROGRAM;

D O I：

10.1038/s41591-022-01891-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

To overcome limitations of previous genome-wide association studies of coronary artery disease, this study incorporates a cohort of individuals containing large fractions of Black and Hispanic individuals to provide a wider view of the genetic landscape of this disease. We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

引用

页码：1679 / +

页数：33

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