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

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.

Investigators

Sharon Lutz

Abbreviation

Nat Genet

Publication Date

2023-09-28

Pubmed ID

37770635

Medium

Print-Electronic

Full Title

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

Authors

Kavousi M, Bos MM, Barnes HJ, Cardenas CLL, Wong D, Lu H, Hodonsky CJ, Landsmeer LPL, Turner AW, Kho M, Hasbani NR, de Vries PS, Bowden DW, Chopade S, Deelen J, Benavente ED, Guo X, Hofer E, Hwang SJ, Lutz SM, Lyytikäinen LP, Slenders L, Smith AV, Stanislawski MA, van Setten J, Wong Q, Yanek LR, Becker DM, Beekman M, Budoff MJ, Feitosa MF, Finan C, Hilliard AT, Kardia SLR, Kovacic JC, Kral BG, Langefeld CD, Launer LJ, Malik S, Hoesein FAAM, Mokry M, Schmidt R, Smith JA, Taylor KD, Terry JG, van der Grond J, van Meurs J, Vliegenthart R, Xu J, Young KA, Zilhão NR, Zweiker R, Assimes TL, Becker LC, Bos D, Carr JJ, Cupples LA, de Kleijn DPV, de Winther M, den Ruijter HM, Fornage M, Freedman BI, Gudnason V, Hingorani AD, Hokanson JE, Ikram MA, Išgum I, Jacobs DR, Kähönen M, Lange LA, Lehtimäki T, Pasterkamp G, Raitakari OT, Schmidt H, Slagboom PE, Uitterlinden AG, Vernooij MW, Bis JC, Franceschini N, Psaty BM, Post WS, Rotter JI, Björkegren JLM, O'Donnell CJ, Bielak LF, Peyser PA, Malhotra R, van der Laan SW, Miller CL