Prioritization of causal genes for coronary artery disease based on cumulative evidence from experimental and in silico studies

• Published in: Scientific reports Vol. 10; no. 1; p. 10486
• Main Authors: Shadrina, Alexandra S., Shashkova, Tatiana I., Torgasheva, Anna A., Sharapov, Sodbo Z., Klarić, Lucija, Pakhomov, Eugene D., Alexeev, Dmitry G., Wilson, James F., Tsepilov, Yakov A., Joshi, Peter K., Aulchenko, Yurii S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.06.2020; Nature Publishing Group
• Subjects: 631/208/2489/144; 692/699/75/593/15; Cardiovascular disease; Computer Simulation; Coronary artery; Coronary Artery Disease - genetics; Coronary vessels; Etiology; Gene expression; Gene loci; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genomics - methods; Heart diseases; Humanities and Social Sciences; Humans; multidisciplinary; Polymorphism, Single Nucleotide - genetics; Quantitative Trait Loci - genetics; Risk Factors; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-67001-w

Genome-wide association studies have led to a significant progress in identification of genomic loci affecting coronary artery disease (CAD) risk. However, revealing the causal genes responsible for the observed associations is challenging. In the present study, we aimed to prioritize CAD-relevant genes based on cumulative evidence from the published studies and our own study of colocalization between eQTLs and loci associated with CAD using SMR/HEIDI approach. Prior knowledge of candidate genes was extracted from both experimental and in silico studies, employing different prioritization algorithms. Our review systematized information for a total of 51 CAD-associated loci. We pinpointed 37 genes in 36 loci. For 27 genes we infer they are causal for CAD, and for 10 further genes we judge them most likely causal. Colocalization analysis showed that for 18 out of these loci, association with CAD can be explained by changes in gene expression in one or more CAD-relevant tissues. Furthermore, for 8 out of 36 loci, existing evidence suggested additional CAD-associated genes. For the remaining 15 loci, we concluded that evidence for gene prioritization remains inconsistent, insufficient, or absent. Our results provide deeper insights into the genetic etiology of CAD and demonstrate knowledge gaps where further research is warranted.