Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease
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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2015-05-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://doi.org/10.1161/JAHA.115.001862 |
| _version_ | 1811206223231451136 |
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| author | Yosuke Moteki Hideaki Onda Hidetoshi Kasuya Taku Yoneyama Yoshikazu Okada Kengo Hirota Maki Mukawa Tadashi Nariai Shohei Mitani Hiroyuki Akagawa |
| author_facet | Yosuke Moteki Hideaki Onda Hidetoshi Kasuya Taku Yoneyama Yoshikazu Okada Kengo Hirota Maki Mukawa Tadashi Nariai Shohei Mitani Hiroyuki Akagawa |
| author_sort | Yosuke Moteki |
| collection | DOAJ |
| description | 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. Methods and 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. |
| first_indexed | 2024-04-12T03:44:08Z |
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| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-12T03:44:08Z |
| publishDate | 2015-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-6a2ea7b878e2401fbdf509c2bbfc70f02022-12-22T03:49:12ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802015-05-0145n/an/a10.1161/JAHA.115.001862Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya DiseaseYosuke Moteki0Hideaki Onda1Hidetoshi Kasuya2Taku Yoneyama3Yoshikazu Okada4Kengo Hirota5Maki Mukawa6Tadashi Nariai7Shohei Mitani8Hiroyuki Akagawa9Department of Neurosurgery Neurological Institute Tokyo Women's Medical University Tokyo JapanDepartment of Neurosurgery Neurological Institute Tokyo Women's Medical University Tokyo JapanDepartment of Neurosurgery Medical Center East Tokyo Women's Medical University Tokyo JapanDepartment of Neurosurgery Neurological Institute Tokyo Women's Medical University Tokyo JapanDepartment of Neurosurgery Neurological Institute Tokyo Women's Medical University Tokyo JapanDepartment of Neurosurgery Medical Center East Tokyo Women's Medical University Tokyo JapanDepartment of Neurosurgery Tokyo Medical and Dental University Tokyo JapanDepartment of Neurosurgery Tokyo Medical and Dental University Tokyo JapanDepartment of Physiology Tokyo Women's Medical University Tokyo JapanDepartment of Neurosurgery Medical Center East Tokyo Women's Medical University Tokyo JapanBackground 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. Methods and 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.https://doi.org/10.1161/JAHA.115.001862cerebrovascular disordersepidemiologygeneticsrisk factors |
| spellingShingle | Yosuke Moteki Hideaki Onda Hidetoshi Kasuya Taku Yoneyama Yoshikazu Okada Kengo Hirota Maki Mukawa Tadashi Nariai Shohei Mitani Hiroyuki Akagawa Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease cerebrovascular disorders epidemiology genetics risk factors |
| title | Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease |
| title_full | Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease |
| title_fullStr | Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease |
| title_full_unstemmed | Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease |
| title_short | Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease |
| title_sort | systematic validation of rnf213 coding variants in japanese patients with moyamoya disease |
| topic | cerebrovascular disorders epidemiology genetics risk factors |
| url | https://doi.org/10.1161/JAHA.115.001862 |
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