Integrative Multi-Omics Mendelian Randomization and Single-Cell Sequencing Prioritize Therapeutic Targets for Coronary Artery Disease

Coronary artery disease (CAD) remains a major global health burden and targeted therapeutic strategies are limited. We integrated two-sample Mendelian randomization (MR) using blood-based expression quantitative trait loci with Bayesian colocalization, external GWAS validation, meta-analysis, single-cell RNA sequencing, cell–cell communication analysis, and phenome-wide MR (Phe-MR). Among the 2460 genes with a significant cis-eQTL, MR identified 26 targets, of which six (PTPN11, FES, VAMP8, LIPA, GGCX and ERP29) were replicated in both cohorts and the meta-analysis. Colocalization supported four (LIPA, GGCX, FES and VAMP8; posterior probability of a shared causal variant (PP.H4) ≥ 0.80 in both cohorts; Tier A), whereas ERP29 (H3-dominant in both cohorts) and PTPN11 (H3-dominant in the discovery cohort; inconclusive in the external cohort) did not reach that threshold (Tier B, MR-replicated without colocalization support). LIPA, GGCX and ERP29 were positively associated with CAD risk (ORs 1.05, 1.12, 1.28); PTPN11, FES and VAMP8 were inversely associated (ORs 0.83, 0.90, 0.90). These genes showed distinct expression across cellular clusters in CAD tissue. Phe-MR across 4698 gene–phenotype combinations identified 24 Bonferroni-significant and 132 false discovery rate (FDR)-significant associations, reported as potential safety signals. The absence of a genetic association does not establish drug safety, and lifelong genetically predicted expression does not estimate transient drug exposure. This study provides genetic evidence for six candidate therapeutic targets for CAD at two clearly different levels of evidence.