Integrative genomic analysis reveals candidate genes and potential molecular mechanisms in carotid atherosclerosis

Carotid intima-media thickness and carotid plaque are key ultrasound-derived indicators of subclinical carotid atherosclerosis. However, the shared genetic architecture linking arterial wall remodeling and plaque formation remains incompletely understood. We integrated summary-level genome-wide association study data for common carotid artery intima-media thickness and carotid plaque using N-weighted multivariate genome-wide association meta-analysis. Significant loci were annotated with FUMA platform. Candidate genes were prioritized using positional mapping, transcriptome-wide association analysis, multi-marker analysis of genomic annotation, and summary-data-based Mendelian randomization combined with the heterogeneity in dependent instruments analysis. Gene ontology enrichment, single-nucleus RNA sequencing, target tractability assessment, and protein network analysis were performed for functional interpretation. Independent gene-level and experimental validation were subsequently performed to further support the prioritized findings. The multivariate analysis identified 12 genome-wide significant loci associated with the shared genetic component of carotid intima-media thickness and carotid plaque. Four complementary prioritization strategies prioritized 31 non-redundant candidate genes. BCAR1 showed the most consistent statistical support across all four methods, while SOX7 and TMEM170A were supported by multiple approaches. Functional enrichment highlighted lipid and lipoprotein metabolism, whereas single-nucleus RNA sequencing showed preferential enrichment of BCAR1 in vascular smooth muscle cells. Independent gene-level and experimental validation further supported BCAR1 , with significant external gene-level association and functional effects of BCAR1 knockdown on oxidized low-density lipoprotein-induced vascular smooth muscle cells responses. By integrating the shared genetic architecture of cIMT and carotid plaque with complementary gene-prioritization, cell-type-resolved, independent gene-level, and functional evidence, this study prioritizes BCAR1 as a genetically supported candidate gene for carotid atherosclerosis. These findings provide a biological and cellular framework for further mechanistic investigation.