P361 - MULTI-ANCESTRY PROTEOME-WIDE MENDELIAN RANDOMIZATION IDENTIFIES RISK PROTEINS FOR INTRACRANIAL ANEURYSMS

Background: Intracranial aneurysms (IA) are cerebrovascular abnormalities causing localized dilations of blood vessels in the brain due to weakened blood vessels or thinning of arterial walls. About 3% of adults harbor unruptured intracranial aneurysms (uIA), where sudden rupture precipitates subarachnoid hemorrhage (SAH), a stroke that can be fatal or lead to permanent neurological deficits in more than half of survivors. Because no pharmacological therapy can prevent aneurysm initiation, growth, or rupture, clinicians must rely on microsurgical clipping or endovascular coiling, both of which entail procedure‑related morbidity. Genome‑wide association studies (GWAS) have mapped 17 IA susceptibility loci, yet the molecular pathways and druggable proteins linking genetic risk to aneurysm biology remain undefined, hindering biomarker development and the design of preventative therapies.

METHODS AND RESULTS: We meta-analyzed IA GWAS (n = 1,943,830 individuals; 23,273 cases and 1,920,557 controls) to capture genetic risk for overall IA, uIA, and SAH in European and East Asian populations. Genetic-ancestry-stratified proteome-wide Mendelian randomization (MR) was performed using cis protein quantitative trait loci for up to 5,000 circulating proteins measured in up to 35,557 individuals from four independent plasma proteomic European cohorts and an East Asian proteomics cohort. Sensitivity analyses with alternative MR methods and colocalization were conducted and implicated seven proteins in IA pathogenesis: ADH4 (odds ratio, OR = 1.56, P= 2.5×10-6), AMBP (OR = 0.62, P = 1.15×10-6), PLEKHA1 (OR = 0.81, P = 3.7×10-5), PKDCC (OR = 0.39, P = 3.8×10-6), GSTO1 (OR = 1.10, P = 2.1×10-7), and FGF5 (OR = 1.11, P = 1.2×10-6) affected overall IA risk, while LIFR (OR = 1.38, P = 4.5×10-6) was specific to SAH. As orthogonal analyses, we performed heterogeneity analyses between uIA and SAH and assessed the contribution of rare exonic variants in these protein-coding regions in a novel French-Canadian cohort (n = 234). We further leveraged the UK Biobank to perform rare variant gene burden testing in 450,000 individuals and conducted observational association analyses with cerebrovascular diseases as additional lines of evidence. Finally, we integrated drug databases from the druggable genome and Open Targets to assess drug repositioning potential of the prioritized protein targets.

Conclusion: By integrating the largest GWAS of intracranial aneurysm across two ancestries with high-resolution population-scale plasma proteomics, we prioritized a set of proteins that causally influence aneurysm formation and rupture. These proteins provide mechanistic biomarkers for clinical risk stratification, informing insights into IA pathophysiology and constituting actionable entry points for drug discovery or repurposing.