ABSTRACT NUMBER: ESOC2026A148 MECHANISTIC CLUSTERS OF INTRACRANIAL ANEURYSM-ASSOCIATED GENETIC VARIANTS DEFINE PATHOGENIC MECHANISMS AND CLINICAL ASSOCIATIONS

Abstract Background and aims Rupture of an intracranial aneurysm (IA) causes aneurysmal subarachnoid hemorrhage. Recently, we identified 60 independent genetic risk variants through genome-wide association study (40,427 cases; 2,898,910 controls, Abstract ESOC2026A159). Here, we investigated through which pathogenic mechanisms these variants act, and their relationship with clinically relevant patient- and aneurysm characteristics. Methods Sixty IA-associated variants were clustered according to their associations with 30 traits (putatively) linked to IA including stroke subtypes and conventional risk factors, derived from independent genome-wide association studies. We created genetic scores representing participants’ liability to each cluster, and all clusters combined. Associations between these scores and patient- and aneurysm characteristics (n = 6,151 IA patients), were assessed using logistic regression, adjusting for sex, cohort, and genetic background. Results Five clusters (7-31 variants each) were found, representing distinct pathogenic mechanisms underlying IA. Clusters were related to cardiovascular risk factors (cluster 1 [CL1]), ischemic stroke-protective mechanisms (CL3), hypertension (CL4) and inflammation (CL5). Overall genetic liability correlated with positive family history (Odds ratio [OR] per standard deviation = 1.11, P = 0.002) and number of IAs (OR = 1.06, P = 3.7x10-8). Cluster-specific associations (Figure) included: Conclusions Clustering IA-associated variants revealed five pathogenic mechanisms, linked to clinically relevant patient- and IA characteristics. We highlight a polygenic component underlying familial IAs, and that IA characteristics vary by genetic liability for distinct pathogenic mechanisms. Conflict of interest None. Figure 1 - belongs to Results