Multi-omics causal inference unravels arterial BCAR1 as a novel protective factor against intracranial aneurysm

Background: Intracranial aneurysm (IA) is a prevalent cerebrovascular disorder, but its pathogenesis remains elusive. Materials and Methods: This study integrated transcriptome-wide association study (TWAS), two-sample Mendelian randomization (MR), Bayesian-based co-localization, and summary-data-based MR (SMR) leveraging arterial cis-eQTL data. These analyses were complemented by single-cell RNA-seq (scRNA-seq) and multiplexed immunofluorescence (mIHC) to prioritize causal genes for IA. Results: Multi-omics analyses nominate BCAR1 as a top candidate, demonstrating a consistent, protective causal effect on IA across methodologies (TWAS P = 0.007 ~ 0.012, MR IVW P = 8.24 × 10 −11 ~ 7.95 × 10 −13 , coloc PPH4 = 0.735 ~ 0.747). In contrast, RP11-252K23.2 is identified as a risk locus (TWAS P = 0.010 ~ 0.013; MR IVW P = 8.66 × 10 −5 ~ 7.44 × 10 −11 ; coloc PPH4 = 0.700 ~ 0.992). ScRNA-seq of human IA domes shows specific enrichment of BCAR1 within a stressed subcluster of vascular smooth muscle cells, a finding validated by mIHC at the protein level. Furthermore, a machine learning-based gene signature centered on BCAR1 robustly predicts IA formation (AUC ≥ 0.926, C-index ≥ 0.926, AUPRC ≥ 0.842). Cross-disease analyses also implicate BCAR1 in atherosclerosis and thoracic aortic aneurysm through co-localization and SMR. Conclusion: Our study establishes BCAR1 as a novel protective factor and potential therapeutic target for IA, underscoring its broader role in maintaining vascular integrity.