학술논문
Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification
Document Type
Original Paper
Author
Kavousi, Maryam; Bos, Maxime M.; Barnes, Hanna J.; Lino Cardenas, Christian L.; Wong, Doris; Lu, Haojie; Hodonsky, Chani J.; Landsmeer, Lennart P. L.; Turner, Adam W.; Kho, Minjung; Hasbani, Natalie R.; de Vries, Paul S.; Bowden, Donald W.; Chopade, Sandesh; Deelen, Joris; Benavente, Ernest Diez; Guo, Xiuqing; Hofer, Edith; Hwang, Shih-Jen; Lutz, Sharon M.; Lyytikäinen, Leo-Pekka; Slenders, Lotte; Smith, Albert V.; Stanislawski, Maggie A.; van Setten, Jessica; Wong, Quenna; Yanek, Lisa R.; Becker, Diane M.; Beekman, Marian; Budoff, Matthew J.; Feitosa, Mary F.; Finan, Chris; Hilliard, Austin T.; Kardia, Sharon L. R.; Kovacic, Jason C.; Kral, Brian G.; Langefeld, Carl D.; Launer, Lenore J.; Malik, Shaista; Hoesein, Firdaus A. A. Mohamed; Mokry, Michal; Schmidt, Reinhold; Smith, Jennifer A.; Taylor, Kent D.; Terry, James G.; van der Grond, Jeroen; van Meurs, Joyce; Vliegenthart, Rozemarijn; Xu, Jianzhao; Young, Kendra A.; Zilhão, Nuno R.; Zweiker, Robert; Assimes, Themistocles L.; Becker, Lewis C.; Bos, Daniel; Carr, J. Jeffrey; Cupples, L. Adrienne; de Kleijn, Dominique P. v.; de Winther, Menno; den Ruijter, Hester M.; Fornage, Myriam; Freedman, Barry I.; Gudnason, Vilmundur; Hingorani, Aroon D.; Hokanson, John E.; Ikram, M. Arfan; Išgum, Ivana; Jacobs, Jr., David R.; Kähönen, Mika; Lange, Leslie A.; Lehtimäki, Terho; Pasterkamp, Gerard; Raitakari, Olli T.; Schmidt, Helena; Slagboom, P. Eline; Uitterlinden, André G.; Vernooij, Meike W.; Bis, Joshua C.; Franceschini, Nora; Psaty, Bruce M.; Post, Wendy S.; Rotter, Jerome I.; Björkegren, Johan L. M.; O’Donnell, Christopher J.; Bielak, Lawrence F.; Peyser, Patricia A.; Malhotra, Rajeev; van der Laan, Sander W.; Miller, Clint L.
Source
Nature Genetics. 55(10):1651-1664
Subject
Language
English
ISSN
1061-4036
1546-1718
1546-1718
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.
Multi-ancestry genome-wide association meta-analysis identifies new risk loci for CAC. Functional evidence implicates candidate causal genes as regulators of smooth muscle cell-mediated calcification.
Multi-ancestry genome-wide association meta-analysis identifies new risk loci for CAC. Functional evidence implicates candidate causal genes as regulators of smooth muscle cell-mediated calcification.