Rho Guanine Nucleotide Exchange Factor Is a Risk Gene for Intracranial Aneurysms.

TitleRho Guanine Nucleotide Exchange Factor Is a Risk Gene for Intracranial Aneurysms.
Publication TypeJournal Article
Year of Publication2018
AuthorsYang, X, Li, J, Fang, Y, Zhang, Z, Jin, D, Chen, X, Zhao, Y, Li, M, Huan, L, Kent, TA, Dong, J-fei, Jiang, R, Yang, S, Jin, L, Zhang, J, Zhong, TP, Yu, F
JournalCirc Genom Precis Med
Date Published2018 Jul
KeywordsAdult, Alleles, Canada, Cohort Studies, Exome, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Intracranial Aneurysm, Male, Middle Aged, Rho Guanine Nucleotide Exchange Factors, Risk Factors, Subarachnoid Hemorrhage

BACKGROUND: Intracranial aneurysm (IA) is usually a late-onset disease, affecting 1% to 3% of the general population and leading to life-threatening subarachnoid hemorrhage. Genetic susceptibility has been implicated in IAs, but the causative genes remain elusive.METHODS: We performed next-generation sequencing in a discovery cohort of 20 Chinese IA patients. Bioinformatics filters were exploited to search for candidate deleterious variants with rare and low allele frequency. We further examined the candidate variants in a multiethnic sample collection of 86 whole exome sequenced unsolved familial IA cases from 3 previously published studies.RESULTS: We identified that the low-frequency variant c.4394C>A_p.Ala1465Asp (rs2298808) of was significantly associated with IA in our Chinese discovery cohort (=7.3×10; odds ratio=7.34). It was subsequently replicated in Japanese familial IA patients (=0.039; odds ratio=4.00; 95% confidence interval=0.832-14.8) and was associated with IA in the large Chinese sample collection comprising 832 sporadic IA-affected and 599 control individuals (=0.041; odds ratio=1.51; 95% confidence interval=1.02-Inf). When combining the sequencing data of all familial IA patients from 4 different ethnicities (ie, Chinese, Japanese, European American, and French-Canadian), we identified a significantly increased mutation burden for (21/106 versus 11/306; =8.1×10; odds ratio=6.6; 95% confidence interval=2.9-15.8) in cases as compared with controls. In zebrafish, was highly expressed in the brain blood vessel. knockdown caused blood extravasation in the brain region. Endothelial lesions were identified exclusively on cerebral blood vessels in the -deficient zebrafish.CONCLUSIONS: Our results provide compelling evidence that is a risk gene for IA.

Alternate JournalCirc Genom Precis Med
PubMed ID29997225
PubMed Central IDPMC6141028
Grant ListR01 HG008115 / HG / NHGRI NIH HHS / United States
R01 HL125957 / HL / NHLBI NIH HHS / United States
R01 NS094535 / NS / NINDS NIH HHS / United States

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