Abstract 15566: Dissecting the Genetic Architecture of Intracranial Aneurysms

Abstract

Introduction: The genetic risk of intracranial aneurysm (IA) development has been ascribed largely to smoking and hypertension. The contribution of IA risk loci to aberrant gene programs within cerebrovascular cell types remains unclear. Hypothesis: We hypothesized that candidate causal genes at IA susceptibility loci are enriched within extracellular matrix producing cell types. Methods: We identified participants enrolled in the Million Veterans Program (MVP) with and without IA. Thirty-two million genotyped and imputed variants were tested for association with IA using mixed effect regression modeling, controlling for age, sex, and population structure prior to external replication and meta-analysis. Candidate causal genes were prioritized through expression quantitative trait loci colocalization and transcriptome wide association studies. We constructed a cerebrovascular single nucleus RNA sequencing (snRNA-seq) dataset and integrated IA summary statistics to compute a ‘disease relevance score’ per nucleus using the scDRS pipeline. Cell type level analysis was used to assess association of cerebrovascular cell types with IA. Results: We identified 3165 participants (2280 European, 627 African, and 258 Hispanic ancestry) with and 592927 without IA in the MVP. After replication and meta-analysis with data from an additional 12273 cases and 591046 controls, we identified 22 loci (5 novel) associated with IA. We prioritized 16 candidate causal genes. Gene expression analysis of snRNA-seq genes revealed enrichment of several candidate genes, including EDNRA and PLCE1 within smooth muscle cells (SMCs) and pericytes. Integration of summary statistics and snRNA-seq data revealed significant association of matrix-producing pericytes and smooth muscle cell populations with IA. Conclusion: Here, we identify novel loci associated with IA and found enrichment of candidate causal genes in pericytes and SMCs. Integration of summary statistics with cerebrovascular snRNA-seq reveals association of cell-types involved in matrix production, suggesting an intrinsic deficit in matrix production and vascular integrity that may drive IA pathogenesis independent of systemic hypertension.