Association of Rare Nonsynonymous Variants in PKD1 and PKD2 with Familial Intracranial Aneurysms in a Japanese Population

Background: Autosomal dominant polycystic kidney disease (ADPKD) caused by deleterious mutations in PKD1 (16p13.3) and PKD2 (4q21) often coexists with intracranial aneurysms (IAs). In this study, we investigated whether IAs without obvious renal diseases were also associated with these ADPKD genes. Methods: We performed next-generation sequencing of the ADPKD genes in 150 Japanese familial IA patients and age- and sex-matched 150 non-IA controls without obvious renal diseases. Rare coding variants for the following association analysis were defined according to allelic frequencies of less than .5% either in our controls or in the 1000 genomes database. Association with IA was evaluated using burden and variance component methods: the weighted-sum statistic (WSS) and the sequence kernel association test (SKAT), respectively. Results: A total of 44 rare candidate variants were confirmed by Sanger sequencing; 26 were identified from 33 patients, whereas 21 were identified from 20 controls. The candidate variants were all missense variants, except for 1 patient's nonsense variant (p.Q924X) in PKD2, and showed consistent association with IA in both burden and variance component tests (odds ratio [ OR] = 1.80; WSS, P = .026; SKAT, P = .044). This association was largely derived from the variants found in the extracellular structural domains of PKD1 (OR = 2.06; WSS, P = .030; SKAT, P = .029). Conclusion: ADPKD genes are susceptibility genes for IA even in patients without ADPKD.