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Rare UNC13B variations and risk of schizophrenia: Whole‐exome sequencing in a multiplex family and follow‐up resequencing and a case–control study
Author(s) -
Egawa Jun,
Hoya Satoshi,
Watanabe Yuichiro,
Nunokawa Ayako,
Shibuya Masako,
Ikeda Masashi,
Inoue Emiko,
Okuda Shujiro,
Kondo Kenji,
Saito Takeo,
Kaneko Naoshi,
Muratake Tatsuyuki,
Igeta Hirofumi,
Iwata Nakao,
Someya Toshiyuki
Publication year - 2016
Publication title -
american journal of medical genetics part b: neuropsychiatric genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.393
H-Index - 126
eISSN - 1552-485X
pISSN - 1552-4841
DOI - 10.1002/ajmg.b.32444
Subject(s) - missense mutation , genetics , exome sequencing , biology , genetic association , multiplex , genetic variation , single nucleotide polymorphism , gene , mutation , genotype
Rare genomic variations inherited in multiplex schizophrenia families are suggested to play a role in the genetic etiology of the disease. To identify rare variations with large effects on the risk of developing schizophrenia, we performed whole‐exome sequencing (WES) in two affected and one unaffected individual of a multiplex family with 10 affected individuals. We also performed follow‐up resequencing of the unc‐13 homolog B ( Caenorhabditis elegans ) ( UNC13B ) gene, a potential risk gene identified by WES, in the multiplex family and undertook a case–control study to investigate association between UNC13B and schizophrenia. UNC13B coding regions (39 exons) from 15 individuals of the multiplex family and 111 affected offspring for whom parental DNA samples were available were resequenced. Rare missense UNC13B variations identified by resequencing were further tested for association with schizophrenia in two independent case–control populations comprising a total of 1,753 patients and 1,602 controls. A rare missense variation (V1525M) in UNC13B was identified by WES in the multiplex family; this variation was present in five of six affected individuals, but not in eight unaffected individuals or one individual of unknown disease status. Resequencing UNC13B coding regions identified five rare missense variations (T103M, M813T, P1349T, I1362T, and V1525M). In the case–control study, there was no significant association between rare missense UNC13B variations and schizophrenia, although single‐variant meta‐analysis indicated that M813T was nominally associated with schizophrenia. These results do not support a contribution of rare missense UNC13B variations to the genetic etiology of schizophrenia in the Japanese population. © 2016 Wiley Periodicals, Inc.