280 A Transcriptome-Wide Association Study of Intracranial Aneurysm Identifies Novel Risk Genes and Overlapping Genetic Architecture With Other Vascular Disorders

INTRODUCTION: Intracranial aneurysms (IAs) are common cerebrovascular lesions with well-documented heritability. Numerous genome-wide association studies (GWAS) have attempted to define IA genetic architecture. However, linking individual risk SNPs from these studies to genes and causal pathways is challenging. To address this, transcriptome-wide association studies (TWAS) directly analyze gene-trait associations. METHODS: We conducted a two-stage TWAS using summary-level GWAS. The discovery cohort was European (GWAS from Bakker et al) and the replication cohort was Japanese (GWAS from Sakaue et al). S-PrediXcan and MASHR-based eQTLs from GTEx v8 were used. We corrected for multiple testing using a study-wide Benjamini-Hochberg FDR <0.05 for each TWAS and for replication. We used less stringent criteria for gene set analysis (GSA) by including genes replicated at a nominal p-value (0.05). GSA was conducted using gene ontology (GO) and a literature review. Additionally, we explored the pleiotropic effects of IA risk genes in other vascular and neurological pathologies, using existing GWAS summary statistics. RESULTS: We identified 20 significant risk genes for IA replicated between cohorts, 12 of which are novel. We used an expanded set of 31 risk genes for GSA. Vascular processes were highly enriched in GO, including vascular smooth muscle function and endothelin signaling. Using GO and literature review, we divided risk genes into five broad categories: vascular function, endothelin signaling, adherens junctions, magnesium levels, and smoking risk. IA risk genes were highly pleiotropic across other vascular and neurological pathologies including, notably, in schizophrenia, migraine, and age-related macular degeneration (AMD). CONCLUSIONS: We conducted the largest TWAS of IA to date, finding 12 novel risk genes and validating 8 previously identified risk genes. We provide plausible causal mechanisms for many of these genes. Finally, we present the first implication of shared genetic architecture between IA and schizophrenia, AMD, and migraine.