title: Rare UNC13B variations and risk of schizophrenia: Whole-exome sequencing in a multiplex family and follow-up resequencing and a case-control study.
abstract: 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.
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Egawa
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hoya
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.|Oojima Hospital, Sanjo, Niigata, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nunokawa
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Inoue
authors.affiliation: Division of Bioinformatics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Shujiro
authors.initials: S
authors.lastname: Okuda
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.|Oojima Hospital, Sanjo, Niigata, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Kaneko
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.|Furumachi Mental Clinic, Niigata, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Muratake
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Igeta
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Someya
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D059472:Exome; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D010375:Pedigree; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; C485548:UNC13B protein, human
keywords: Japanese; gene-based analysis; meta-analysis; missense variation