Rare genetic variants in PKD1 and SMAD2 are associated with intracranial aneurysms in the general population

Introduction: Family studies identified several rare genetic risk variants for intracranial aneurysms (IAs) and aneurysmal subarachnoid hemorrhage (ASAH). In addition, certain monogenic disorders caused by rare penetrant genetic variants predispose individuals to IA and ASAH. We investigated the effect of these variants on IA and ASAH in the general population. Patients and Methods: We tested the association between genetic variants within IA-associated genes and IA and ASAH using a burden test, sequence kernel association test (SKAT), and variant-level aggregated Cauchy association test (ACAT-V) in the UK Biobank. Variants were stratified by allele frequency and predicted impact on the protein structure. Sensitivity analyses were performed on only ASAH patients and excluding participants diagnosed with an aforementioned monogenic disorder. Results: In the group of 1656 IA cases, including 928 ASAH cases, and 391,948 controls, associations were identified for ultrarare variants with moderate or high impact in PKD1 (odds ratio (OR) = 1.42; 95% confidence interval (95% CI)= 1.06–1.85, p = 4.28 × 10⁻⁷ (SKAT)) and SMAD2 (OR = 4.89; 95% CI = 1.63–11.05, p = 7.10 × 10⁻⁵ (SKAT)). Upon excluding participants diagnosed with the respective monogenic disorders, these associations remained. When considering only ASAH cases, the association with SMAD2 was similar (OR = 4.85; 95% CI = 1.02–13.7; p = 9.0 × 10⁻⁴) while for PKD1 the association diminished (OR = 1.29; 95% CI = 0.85–1.87; p = 0.043). Discussion and Conclusion: Ultrarare damaging variants in PKD1, a gene causing autosomal dominant polycystic kidney disease, and SMAD2, a gene causing Loeys-Dietz syndrome, were associated with IA in the general population, even in the absence of a diagnosis of these disorders. Our results may contribute to the development of genetic screening methods for IA in a clinical setting.