Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification

Maryam Kavousi, Maxime M. Bos, Hanna J. Barnes, Christian L. Lino Cardenas, Doris Wong, Haojie Lu, Chani J. Hodonsky, Lennart P.L. Landsmeer, Adam W. Turner, Minjung Kho, Natalie R. Hasbani, Paul S. de Vries, Donald W. Bowden, Sandesh Chopade, Joris Deelen, Ernest Diez Benavente, Xiuqing Guo, Edith Hofer, Shih Jen Hwang, Sharon M. LutzLeo Pekka Lyytikäinen, Lotte Slenders, Albert V. Smith, Maggie A. Stanislawski, Jessica van Setten, Quenna Wong, Lisa R. Yanek, Diane M. Becker, Marian Beekman, Matthew J. Budoff, Mary F. Feitosa, Chris Finan, Austin T. Hilliard, Sharon L.R. Kardia, Jason C. Kovacic, Brian G. Kral, Carl D. Langefeld, Lenore J. Launer, Shaista Malik, Firdaus A.A.Mohamed Hoesein, Michal Mokry, Reinhold Schmidt, Jennifer A. Smith, Kent D. Taylor, James G. Terry, Jeroen van der Grond, Joyce van Meurs, Rozemarijn Vliegenthart, Jianzhao Xu, Kendra A. Young, Nuno R. Zilhão, Robert Zweiker, Themistocles L. Assimes, Lewis C. Becker, Daniel Bos, J. Jeffrey Carr, L. Adrienne Cupples, Dominique P.v. de Kleijn, Menno de Winther, Hester M. den Ruijter, Myriam Fornage, Barry I. Freedman, Vilmundur Gudnason, Aroon D. Hingorani, John E. Hokanson, M. Arfan Ikram, Ivana Išgum, David R. Jacobs, Mika Kähönen, Leslie A. Lange, Terho Lehtimäki, Gerard Pasterkamp, Olli T. Raitakari, Helena Schmidt, P. Eline Slagboom, André G. Uitterlinden, Meike W. Vernooij, Joshua C. Bis, Nora Franceschini, Bruce M. Psaty, Wendy S. Post, Jerome I. Rotter, Johan L.M. Björkegren, Christopher J. O’Donnell, Lawrence F. Bielak, Patricia A. Peyser, Rajeev Malhotra, Sander W. van der Laan, Clint L. Miller

Research output: Contribution to journalArticleScientificpeer-review

12 Citations (Scopus)

Abstract

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Original languageEnglish
Pages (from-to)1651-1664
Number of pages14
JournalNature Genetics
Volume55
Issue number10
DOIs
Publication statusPublished - 2023
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 3

ASJC Scopus subject areas

  • Genetics

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