title: Rare truncating variations and risk of schizophrenia: Whole-exome sequencing in three families with affected siblings and a three-stage follow-up study in a Japanese population.
abstract: Rare inherited variations in multiplex families with schizophrenia are suggested to play a role in the genetic etiology of schizophrenia. To further investigate the role of rare inherited variations, we performed whole-exome sequencing (WES) in three families, each with two affected siblings. We also performed a three-stage follow-up case-control study in a Japanese population with a total of 2617 patients and 2396 controls. WES identified 15 rare truncating variations that were variously present in the two affected siblings in each family. These variations did not necessarily segregate with schizophrenia within families, and they were different in each family. In the follow-up study, four variations (NWD1 W169X, LCORL R7fsX53, CAMK2B L497fsX497, and C9orf89 Q102X) had a higher mutant allele frequency in patients compared with controls, although these associations were not significant in the combined population, which comprised the first-, second- and third-stage populations. These results do not support a contribution of the rare truncating variations identified in the three families to the genetic etiology of schizophrenia.
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan. Electronic address: yuichiro@med.niigata-u.ac.jp.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan; Oojima Hospital, 5103 Oojima, Sanjo, Niigata 955-0094, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nunokawa
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Shibuya
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Akitoyo
authors.initials: A
authors.lastname: Hishimoto
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Egawa
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan; Oojima Hospital, 5103 Oojima, Sanjo, Niigata 955-0094, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Kaneko
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan; Furumachi Mental Clinic, 608 Furumachidori-gobancho, Chuo-ku, Niigata 951-8063, Japan.
authors.forename: Tatsuyuki
authors.initials: T
authors.lastname: Muratake
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Saito
authors.affiliation: Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
authors.forename: Ayu
authors.initials: A
authors.lastname: Shimasaki
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Igeta
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Inoue
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hoya
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Sugai
authors.affiliation: Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Sora
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 757 Asahimachidori-Ichibancho, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Someya
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics* / Q000523:psychology; D016022:Case-Control Studies; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*; D017421:Sequence Analysis / Q000379:methods; D035781:Siblings
keywords: Affected siblings; Case-control study; Rare truncating variations; Schizophrenia; Whole-exome sequencing