ABSTRACT NUMBER: ESOC2026A172 GENETIC PREDISPOSITION TO INTRACRANIAL ANEURYSMS IS DRIVEN BY VASCULAR SMOOTH MUSCLE CELLS AND VASCULAR ENDOTHELIAL CELLS

Abstract Background and aims Intracranial aneurysms (IAs), which primarily develop on the arteries of the circle of Willis, cause an aneurysmal subarachnoid haemorrhage when ruptured. Previous genetic studies, including genome-wide association studies (GWAS), have shown that IA formation has a substantial genetic component. However, it remains unclear which cell types significantly contribute to the pathogenesis of IA. We performed a cell type enrichment analysis using a newly generated single-cell RNA sequencing (scRNA-seq) dataset and the largest genetic cohort of IA patients. Methods We generated the first scRNA-seq dataset of human intracranial arteries of the circle of Willis, which comprises seven post-mortem samples obtained from the Netherlands Brain Bank. We studied cell type-specific genetic liability to IA by integrating our gene expression data with European GWAS summary statistics for IA (33,956 cases and 2,447,379 controls, Abstract ESOC2026A159). This analysis was performed using the CELLECT pipeline. Results We obtained high-quality gene expression profiles of 55,371 cells representing seven distinct major cell types. Genes specific for vascular endothelial cells and vascular smooth muscle cells were enriched for IA-associated genes (Figure). When using sex-stratified GWAS results, we found enrichment for vascular smooth muscle cells in women, but not in men. Conclusions Our analyses indicate that vascular smooth muscle cells and vascular endothelial cells play a major role in the genetic predisposition for IA, whereas we do not find evidence for a pathogenic role for other cell types, such as perivascular fibroblasts. Notably, vascular smooth muscle cells may contribute more to IA pathogenesis in women than in men. Conflict of interest None Figure 1 - belongs to Results