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. 2017 Mar;22(3):430-440.
doi: 10.1038/mp.2016.88. Epub 2016 May 31.

High-resolution copy number variation analysis of schizophrenia in Japan

I Kushima  1   2 , B Aleksic  2 , M Nakatochi  3 , T Shimamura  4 , T Shiino  2 , A Yoshimi  2 , H Kimura  2 , Y Takasaki  2 , C Wang  2 , J Xing  2 , K Ishizuka  2 , T Oya-Ito  2 , Y Nakamura  2 , Y Arioka  2   5 , T Maeda  2 , M Yamamoto  2 , M Yoshida  2 , H Noma  2 , S Hamada  2 , M Morikawa  2 , Y Uno  2 , T Okada  2 , T Iidaka  2 , S Iritani  2 , T Yamamoto  6 , M Miyashita  7 , A Kobori  7 , M Arai  7 , M Itokawa  8 , M-C Cheng  9 , Y-A Chuang  9 , C-H Chen  10   11 , M Suzuki  12 , T Takahashi  12 , R Hashimoto  13   14 , H Yamamori  14 , Y Yasuda  14 , Y Watanabe  15 , A Nunokawa  15 , T Someya  15 , M Ikeda  16 , T Toyota  17 , T Yoshikawa  17 , S Numata  18 , T Ohmori  18 , S Kunimoto  2 , D Mori  2   19 , N Iwata  16 , N Ozaki  2
Affiliations

High-resolution copy number variation analysis of schizophrenia in Japan

I Kushima et al. Mol Psychiatry. 2017 Mar.

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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