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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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.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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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) doi:10.1038/mp.2016.88
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