title: High-resolution copy number variation analysis of schizophrenia in Japan.
abstract: Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.
authors.affiliation: Institute for Advanced Research, Nagoya University, Nagoya, Japan.|Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Kushima
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: B
authors.identifier: 0000-0001-8982-4580
authors.initials: B
authors.lastname: Aleksic
authors.affiliation: Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors.forename: M
authors.identifier: 0000-0002-1838-4837
authors.initials: M
authors.lastname: Nakatochi
authors.affiliation: Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shiino
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshimi
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Takasaki
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Xing
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ishizuka
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.identifier: 0000-0001-6921-4566
authors.initials: T
authors.lastname: Oya-Ito
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Arioka
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Noma
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hamada
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Morikawa
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Uno
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.identifier: 0000-0002-6199-8711
authors.initials: T
authors.lastname: Iidaka
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Iritani
authors.affiliation: Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Miyashita
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kobori
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Arai
authors.affiliation: Center for Medical Cooperation, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Itokawa
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Cheng
authors.affiliation: Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan.
authors.forename: Y-A
authors.initials: YA
authors.lastname: Chuang
authors.affiliation: Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan.|Department and Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Japan.|Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: R
authors.identifier: 0000-0002-5941-4238
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yamamori
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Nunokawa
authors.affiliation: Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Someya
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ikeda
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Toyota
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Numata
authors.affiliation: Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ohmori
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kunimoto
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.|Brain and Mind Research Center, Nagoya University, Nagoya, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Mori
authors.affiliation: Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Iwata
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ozaki
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D055028:Comparative Genomic Hybridization / Q000379:methods; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007564:Japan; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*