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
Bakker et al. (Fri,) studied this question.