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High-resolution copy number variation analysis of schizophrenia in Japan

Molecular Psychiatry volume 22, pages 430–440 (2017)Cite this article

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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.

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Acknowledgements

We thank the patients and their families for participating in this study. This research was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Ministry of Health, Labor and Welfare of Japan; 'Integrated research on neuropsychiatric disorders' carried out under the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development, AMED; the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from AMED; Innovative Areas 'Glial assembly: a new regulatory machinery of brain function and disorders'; Innovative Areas 'Comprehensive Brain Science Network'; Research Group For Schizophrenia; SENSHIN Medical Research Foundation; and The Uehara Memorial Foundation. The ClinVar accession numbers for the clinically significant CNVs identified in patients are SCV000263416–SCV000263544.

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  1. I Kushima and B Aleksic: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Advanced Research, Nagoya University, Nagoya, Japan

    I Kushima

  2. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan

    I Kushima, B Aleksic, T Shiino, A Yoshimi, H Kimura, Y Takasaki, C Wang, J Xing, K Ishizuka, T Oya-Ito, Y Nakamura, Y Arioka, T Maeda, M Yamamoto, M Yoshida, H Noma, S Hamada, M Morikawa, Y Uno, T Okada, T Iidaka, S Iritani, S Kunimoto, D Mori & N Ozaki

  3. Bioinformatics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

    M Nakatochi

  4. Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Shimamura

  5. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

    Y Arioka

  6. Department of Legal Medicine and Bioethics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    T Yamamoto

  7. Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    M Miyashita, A Kobori & M Arai

  8. Center for Medical Cooperation, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    M Itokawa

  9. Department of Psychiatry, Yuli Mental Health Research Center, Yuli Branch, Taipei Veterans General Hospital, Hualien, Taiwan

    M -C Cheng & Y -A Chuang

  10. Department of Psychiatry, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan

    C -H Chen

  11. Department and Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan

    C -H Chen

  12. Department of Neuropsychiatry, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan

    M Suzuki & T Takahashi

  13. Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Japan

    R Hashimoto

  14. Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Japan

    R Hashimoto, H Yamamori & Y Yasuda

  15. Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Y Watanabe, A Nunokawa & T Someya

  16. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan

    M Ikeda & N Iwata

  17. Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan

    T Toyota & T Yoshikawa

  18. Department of Psychiatry, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

    S Numata & T Ohmori

  19. Brain and Mind Research Center, Nagoya University, Nagoya, Japan

    D Mori

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  1. I Kushima
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Corresponding author

Correspondence to N Ozaki.

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Kushima, I., Aleksic, B., Nakatochi, M. et al. High-resolution copy number variation analysis of schizophrenia in Japan. Mol Psychiatry 22, 430–440 (2017). https://doi.org/10.1038/mp.2016.88

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