Large-Scale Genome-Wide Association Study of Coronary Artery Disease in Genetically Diverse Populations

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Citation

Tcheandjieu, Catherine; Zhu, Xiang; Hilliard, Austin T.; Clarke, Shoa L.; Napolioni, Valerio; Ma, Shining; Lee, Kyung M.; Fang, Huaying; Chen, Fei; & Lu, Yingchang, et al. (2022). Large-Scale Genome-Wide Association Study of Coronary Artery Disease in Genetically Diverse Populations. Nature Medicine, 28(8), 1679-1692. PMCID: PMC9419655

Abstract

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.

URL

http://dx.doi.org/10.1038/s41591-022-01891-3

Reference Type

Journal Article

Year Published

2022

Journal Title

Nature Medicine

Author(s)

Tcheandjieu, Catherine
Zhu, Xiang
Hilliard, Austin T.
Clarke, Shoa L.
Napolioni, Valerio
Ma, Shining
Lee, Kyung M.
Fang, Huaying
Chen, Fei
Lu, Yingchang
Tsao, Noah L.
Raghavan, Sridharan
Koyama, Satoshi
Gorman, Bryan R.
Vujkovic, Marijana
Klarin, Derek
Levin, Michael G.
Sinnott-Armstrong, Nasa
Wojcik, Genevieve L.
Plomondon, Mary E.
Maddox, Thomas M.
Waldo, Stephen W.
Bick, Alexander G.
Pyarajan, Saiju
Huang, Jie
Song, Rebecca J.
Ho, Yuk-Lam
Buyske, Steven G.
Kooperberg, Charles
Haessler, Jeffrey
Loos, Ruth J. F.
Do, Ron
Verbanck, Marie
Chaudhary, Kumardeep
North, Kari E.
Avery, Christy L.
Graff, Mariaelisa
Haiman, Christopher A.
Le Marchand, Loïc
Wilkens, Lynne R.
Bis, Joshua C.
Leonard, Hampton
Shen, Botong
Lange, Leslie A.
Giri, Ayush
Dikilitas, Ozan
Kullo, Iftikhar J.
Stanaway, Ian B.
Jarvik, Gail P.
Gordon, Adam S.
Hebbring, Scott
Namjou, Bahram
Kaufman, Kenneth M.
Ito, Kaoru
Ishigaki, Kazuyoshi
Kamatani, Yoichiro
Verma, Shefali S.
Ritchie, Marylyn D.
Kember, Rachel L.
Baras, Aris
Lotta, Luca A., for Regeneron Genetics Center, ARDIoGRAMplusC4D Consortium, Biobank Japan, and Million Veteran Program
Kathiresan, Sekar
Hauser, Elizabeth R.
Miller, Donald R.
Lee, Jennifer S.
Saleheen, Danish
Reaven, Peter D.
Cho, Kelly
Gaziano, Michael J.
Natarajan, Pradeep
Huffman, Jennifer E.
Voight, Benjamin F.
Rader, Daniel J.
Chang, Kyong-Mi
Lynch, Julie A.
Damrauer, Scott M.
Wilson, Peter W. F.
Tang, Hua
Sun, Yan V.
Tsao, Philip S.
O'Donnell, Christopher J.
Assimes, Themistocles L.

Article Type

Regular

PMCID

PMC9419655

Data Set/Study

Million Veteran Program

Continent/Country

United States of America

State

Nonspecific

Race/Ethnicity

White
Black
Hispanic

ORCiD

Avery - 0000-0002-1044-8162
Graff - 0000-0001-6380-1735