Genetic contribution to coronary artery disease (CAD) remains largely unillustrated. Although transcriptomic profiles have identified dozens of genes that are differentially expressed in normal and atherosclerotic vessels, whether those genes are genetically associated with CAD remains to be determined. Here, we combined genetic association studies, transcriptome profiles and in vitro and in vivo functional experiments to identify novel susceptibility genes for CAD. Through an integrative analysis of transcriptome profiles with genome-wide association studies for CAD, we obtained 18 candidate genes and selected one representative SNP for each gene for multi-centered validations. We identified an intragenic SNP, rs1056515 in RGS5 gene (OR = 1.17, 95%CI =1.10-1.24, P = 3.72 × 10-8) associated with CAD at genome-wide significance. Rare genetic variants in linkage disequilibrium with rs1056515 were identified in CAD patients leading to a decreased expression of RGS5. The decreased expression was also observed in atherosclerotic vessels and endothelial cells treated by various cardiovascular risk factors. Through siRNA knockdown and adenoviral overexpression, we further showed that RGS5 regulated endothelial inflammation, vascular remodeling, as well as canonical NF-κB signaling activation. Moreover, CXCL12, a specific downstream target of the noncanonical NF-κB pathway, was strongly affected by RGS5. However, the p100 processing, a well-documented marker for noncanonical NF-κB pathway activation, was not altered, suggesting an existence of a novel mechanism by which RGS5 regulates CXCL12. We identified RGS5 as a novel susceptibility gene for CAD and showed that the decreased expression of RGS5 impaired endothelial cell function and functionally contributed to atherosclerosis through a variety of molecular mechanisms. How RGS5 regulates the expression of CXCL12 needs further studies. Current knowledge of the genetic contribution to CAD and mechanism underlying CAD associated loci identified in GWAS are both limited. Our study identifies a common variant rs1056515 as a genetic marker for CAD and rare variants in LD with rs1056515 leading to decreased expression of RGS5, which contributes to atherosclerosis by impairing endothelial cell function. Our study provides novel means for (i) Identification of patients at risk of CAD, (ii) Understanding the basis for disease pathogenesis, and (iii) development of new therapeutic strategies for the treatment of the disease. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions please email: journals.permissions@oup.com.