title: Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease.
abstract: BACKGROUND
  A founder variant of RNF213, p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease (MMD) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other RNF213 variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with MMD.
  
  
  RESULTS
  To detect variants of RNF213, all coding exons were sequenced in 27 Japanese MMD patients without p.R4810K. We also validated all previously reported variants in our case-control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population-based controls. Forty-six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with MMD. We conducted a variable threshold test using Combined Annotation-Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum P=0.045).
  
  
  CONCLUSIONS
  Not only p.4810K but also other functional missense variants of RNF213 conferred susceptibility to MMD. Our analysis also revealed that ≈20% of Japanese MMD patients did not harbor susceptibility variants of RNF213, indicating the presence of other susceptibility genes for MMD.
authors.affiliation: Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (Y.M., H.O., T.Y., Y.O.).
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Moteki
authors.affiliation: Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (Y.M., H.O., T.Y., Y.O.).
authors.forename: Hideaki
authors.initials: H
authors.lastname: Onda
authors.affiliation: Department of Neurosurgery, Medical Center East, Tokyo Women's Medical University, Tokyo, Japan (H.K., K.H., H.A.) Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan (H.K., K.H., S.M., H.A.).
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kasuya
authors.affiliation: Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (Y.M., H.O., T.Y., Y.O.).
authors.forename: Taku
authors.initials: T
authors.lastname: Yoneyama
authors.affiliation: Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan (Y.M., H.O., T.Y., Y.O.).
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Neurosurgery, Medical Center East, Tokyo Women's Medical University, Tokyo, Japan (H.K., K.H., H.A.) Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan (H.K., K.H., S.M., H.A.).
authors.forename: Kengo
authors.initials: K
authors.lastname: Hirota
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan (M.M., T.N.).
authors.forename: Maki
authors.initials: M
authors.lastname: Mukawa
authors.affiliation: Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan (M.M., T.N.).
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nariai
authors.affiliation: Department of Physiology, Tokyo Women's Medical University, Tokyo, Japan (S.M.) Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan (H.K., K.H., S.M., H.A.).
authors.forename: Shohei
authors.initials: S
authors.lastname: Mitani
authors.affiliation: Department of Neurosurgery, Medical Center East, Tokyo Women's Medical University, Tokyo, Japan (H.K., K.H., H.A.) Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan (H.K., K.H., S.M., H.A.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Akagawa
mesh_terms: D000251:Adenosine Triphosphatases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D059472:Exome / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D009072:Moyamoya Disease / Q000235:genetics*; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C557998:RNF213 protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases
keywords: cerebrovascular disorders; epidemiology; genetics; risk factors