title: RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population.
abstract: Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease.
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
authors.forename: Sirui
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada.
authors.forename: Amirthagowri
authors.initials: A
authors.lastname: Ambalavanan
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rochefort
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Faculty of Medicine, McGill University, Montréal, QC H3A 0G4, Canada.
authors.forename: Pingxing
authors.initials: P
authors.lastname: Xie
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Cynthia V
authors.initials: CV
authors.lastname: Bourassa
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Pascale
authors.initials: P
authors.lastname: Hince
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Dionne-Laporte
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Spiegelman
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Gan-Or
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Cathy
authors.initials: C
authors.lastname: Mirarchi
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada.
authors.forename: Vessela
authors.initials: V
authors.lastname: Zaharieva
authors.affiliation: Department of Neurological Sciences, Centre Hospitalier Universitaire de Québec, Québec, QC G1V 0A6, Canada; Department of Medicine, Faculty of Medicine, Laval University, Québec, QC G1V 0A6, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dupré
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Yoshida Konoecho, Kyoto 606-8501, Japan.
authors.forename: Hatasu
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Yoshida Konoecho, Kyoto 606-8501, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Yoshida Konoecho, Kyoto 606-8501, Japan.
authors.forename: Kouji
authors.initials: K
authors.lastname: Harada
authors.affiliation: Department of Health and Environmental Sciences, Graduate School of Medicine, Kyoto University, Yoshida Konoecho, Kyoto 606-8501, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Koizumi
authors.affiliation: Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Centre de Recherche, Institut Universitaire en Santé Mentale de Montréal, Montréal QC H1N 3M5, Canada.
authors.forename: Lan
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Dion
authors.affiliation: Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 0G4, Canada. Electronic address: guy.rouleau@mcgill.ca.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D002170:Canada; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D002532:Intracranial Aneurysm / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases