Genome-wide association studies have identified 161 genetic variants associated with coronary artery disease (CAD), but the causal genes and biological pathways remain unknown at most loci. This knowledge is critical to optimize precision medicine strategies and develop new drugs for CAD. Here, we performed multiple pooled CRISPR screens to test the impact of CAD-associated genetic variants on vascular endothelial cell functions. Using CRISPR knockout, inhibition and activation, we targeted 1998 variants at 83 CAD loci to assess their effect by flow cytometry on three adhesion proteins (E-selectin, ICAM1, VCAM1) and three key endothelial functions (nitric oxide and reactive oxygen species production, calcium signaling). At a false discovery rate ≤10%, we identified 42 significant variants located within 26 CAD loci. Although a few of these loci include genes previously characterized in endothelial cells (e.g. MIA3/AIDA, FURIN, ARHGEF26, ADAMTS7), most are implicated in endothelial dysfunction for the first time. Detailed cellular and molecular characterization of the RNA helicase DHX38, as well as CRISPR-mediated over-expression experiments at the FURIN/FES, CCDC92/ZNF664 and CNNM2 loci, revealed a strong effect on vascular endothelial cell senescence. Our findings implicate many CAD-associated loci in the regulation of atherosclerosis-related endothelial functions and offer new insights into how modulating these functions could help prevent or treat CAD. Overall design: Human, immortalized teloHAEC cell lines stably expressing different Cas9 variants (Cas9, dCas9-KRAB (CRISPRi), dCas9-VP64 (CRISPRa)) were infected with lentiviruses containing sgRNA targeting candidate loci and LD proxies for coronary artery disease (CAD) in the human genome. Cells were selected via anibiotic selection to remove cells not infected with an sgRNA. TeloHAEC expressing Cas9 or dCas9-KRAB (CRISPRi) were stimulated with TNFa to induce a proinflammatory response, whereas teloHAEC expressing CRISPRa were not stimulated. After 5 (CRISPRa) or 7 (Cas9 or dCas9-KRAB (CRISPRi)) days respectively, cells were stained and sorted for endothelial adhesion molecules (E-SELECTIN, ICAM1, VCAM1) or physiological readouts (NO, ROS, Ca2+). The top and bottom 10% of cells for each FACS marker were collected, gDNA extracted, sgRNA sequences amplified via PCR and sequenced.