High-resolution copy number variation analysis of schizophrenia in Japan

I. Kushima, B. Aleksic, M. Nakatochi, T. Shimamura, 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. MorikawaY. Uno, T. Okada, T. Iidaka, S. Iritani, T. Yamamoto, M. Miyashita, A. Kobori, M. Arai, M. Itokawa, M. C. Cheng, Y. A. Chuang, C. H. Chen, M. Suzuki, T. Takahashi, R. Hashimoto, H. Yamamori, Y. Yasuda, Y. Watanabe, A. Nunokawa, T. Someya, Masashi Ikeda, T. Toyota, T. Yoshikawa, S. Numata, T. Ohmori, S. Kunimoto, D. Mori, Nakao Iwata, N. Ozaki

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)430-440
Number of pages11
JournalMolecular Psychiatry
Volume22
Issue number3
DOIs
Publication statusPublished - 01-03-2017

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Schizophrenia
Japan
Odds Ratio
Phenotype
Comparative Genomic Hybridization
Calcium Signaling
Monomeric GTP-Binding Proteins
Genetic Heterogeneity
Genomic Instability
X Chromosome
Aneuploidy
Synapses
Genes
Oxidative Stress
Phosphotransferases
Genome
Population

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Kushima, I., Aleksic, B., Nakatochi, M., Shimamura, T., Shiino, T., Yoshimi, A., ... Ozaki, N. (2017). High-resolution copy number variation analysis of schizophrenia in Japan. Molecular Psychiatry, 22(3), 430-440. https://doi.org/10.1038/mp.2016.88
Kushima, I. ; Aleksic, B. ; Nakatochi, M. ; Shimamura, T. ; Shiino, T. ; Yoshimi, A. ; Kimura, H. ; Takasaki, Y. ; Wang, C. ; Xing, J. ; Ishizuka, K. ; Oya-Ito, T. ; Nakamura, Y. ; Arioka, Y. ; Maeda, T. ; Yamamoto, M. ; Yoshida, M. ; Noma, H. ; Hamada, S. ; Morikawa, M. ; Uno, Y. ; Okada, T. ; Iidaka, T. ; Iritani, S. ; Yamamoto, T. ; Miyashita, M. ; Kobori, A. ; Arai, M. ; Itokawa, M. ; Cheng, M. C. ; Chuang, Y. A. ; Chen, C. H. ; Suzuki, M. ; Takahashi, T. ; Hashimoto, R. ; Yamamori, H. ; Yasuda, Y. ; Watanabe, Y. ; Nunokawa, A. ; Someya, T. ; Ikeda, Masashi ; Toyota, T. ; Yoshikawa, T. ; Numata, S. ; Ohmori, T. ; Kunimoto, S. ; Mori, D. ; Iwata, Nakao ; Ozaki, N. / High-resolution copy number variation analysis of schizophrenia in Japan. In: Molecular Psychiatry. 2017 ; Vol. 22, No. 3. pp. 430-440.
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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.",
author = "I. Kushima and B. Aleksic and M. Nakatochi and T. Shimamura and T. Shiino and A. Yoshimi and H. Kimura and Y. Takasaki and C. Wang and J. Xing and K. Ishizuka and T. Oya-Ito and Y. Nakamura and Y. Arioka and T. Maeda and M. Yamamoto and M. Yoshida and H. Noma and S. Hamada and M. Morikawa and Y. Uno and T. Okada and T. Iidaka and S. Iritani and T. Yamamoto and M. Miyashita and A. Kobori and M. Arai and M. Itokawa and Cheng, {M. C.} and Chuang, {Y. A.} and Chen, {C. H.} and M. Suzuki and T. Takahashi and R. Hashimoto and H. Yamamori and Y. Yasuda and Y. Watanabe and A. Nunokawa and T. Someya and Masashi Ikeda and T. Toyota and T. Yoshikawa and S. Numata and T. Ohmori and S. Kunimoto and D. Mori and Nakao Iwata and N. Ozaki",
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Kushima, I, Aleksic, B, Nakatochi, M, Shimamura, T, Shiino, T, Yoshimi, A, Kimura, H, Takasaki, Y, Wang, C, Xing, J, Ishizuka, K, Oya-Ito, T, Nakamura, Y, Arioka, Y, Maeda, T, Yamamoto, M, Yoshida, M, Noma, H, Hamada, S, Morikawa, M, Uno, Y, Okada, T, Iidaka, T, Iritani, S, Yamamoto, T, Miyashita, M, Kobori, A, Arai, M, Itokawa, M, Cheng, MC, Chuang, YA, Chen, CH, Suzuki, M, Takahashi, T, Hashimoto, R, Yamamori, H, Yasuda, Y, Watanabe, Y, Nunokawa, A, Someya, T, Ikeda, M, Toyota, T, Yoshikawa, T, Numata, S, Ohmori, T, Kunimoto, S, Mori, D, Iwata, N & Ozaki, N 2017, 'High-resolution copy number variation analysis of schizophrenia in Japan', Molecular Psychiatry, vol. 22, no. 3, pp. 430-440. https://doi.org/10.1038/mp.2016.88

High-resolution copy number variation analysis of schizophrenia in Japan. / Kushima, I.; Aleksic, B.; Nakatochi, M.; Shimamura, T.; Shiino, T.; Yoshimi, A.; Kimura, H.; Takasaki, Y.; Wang, C.; Xing, J.; Ishizuka, K.; Oya-Ito, T.; Nakamura, Y.; Arioka, Y.; Maeda, T.; Yamamoto, M.; Yoshida, M.; Noma, H.; Hamada, S.; Morikawa, M.; Uno, Y.; Okada, T.; Iidaka, T.; Iritani, S.; Yamamoto, T.; Miyashita, M.; Kobori, A.; Arai, M.; Itokawa, M.; Cheng, M. C.; Chuang, Y. A.; Chen, C. H.; Suzuki, M.; Takahashi, T.; Hashimoto, R.; Yamamori, H.; Yasuda, Y.; Watanabe, Y.; Nunokawa, A.; Someya, T.; Ikeda, Masashi; Toyota, T.; Yoshikawa, T.; Numata, S.; Ohmori, T.; Kunimoto, S.; Mori, D.; Iwata, Nakao; Ozaki, N.

In: Molecular Psychiatry, Vol. 22, No. 3, 01.03.2017, p. 430-440.

Research output: Contribution to journalArticle

TY - JOUR

T1 - High-resolution copy number variation analysis of schizophrenia in Japan

AU - Kushima, I.

AU - Aleksic, B.

AU - Nakatochi, M.

AU - Shimamura, T.

AU - Shiino, T.

AU - Yoshimi, A.

AU - Kimura, H.

AU - Takasaki, Y.

AU - Wang, C.

AU - Xing, J.

AU - Ishizuka, K.

AU - Oya-Ito, T.

AU - Nakamura, Y.

AU - Arioka, Y.

AU - Maeda, T.

AU - Yamamoto, M.

AU - Yoshida, M.

AU - Noma, H.

AU - Hamada, S.

AU - Morikawa, M.

AU - Uno, Y.

AU - Okada, T.

AU - Iidaka, T.

AU - Iritani, S.

AU - Yamamoto, T.

AU - Miyashita, M.

AU - Kobori, A.

AU - Arai, M.

AU - Itokawa, M.

AU - Cheng, M. C.

AU - Chuang, Y. A.

AU - Chen, C. H.

AU - Suzuki, M.

AU - Takahashi, T.

AU - Hashimoto, R.

AU - Yamamori, H.

AU - Yasuda, Y.

AU - Watanabe, Y.

AU - Nunokawa, A.

AU - Someya, T.

AU - Ikeda, Masashi

AU - Toyota, T.

AU - Yoshikawa, T.

AU - Numata, S.

AU - Ohmori, T.

AU - Kunimoto, S.

AU - Mori, D.

AU - Iwata, Nakao

AU - Ozaki, N.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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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Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A et al. High-resolution copy number variation analysis of schizophrenia in Japan. Molecular Psychiatry. 2017 Mar 1;22(3):430-440. https://doi.org/10.1038/mp.2016.88