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Schizophr Bull. 2014 Nov;40(6):1285-99. doi: 10.1093/schbul/sbu045. Epub 2014 Mar 24.

Systematic prioritization and integrative analysis of copy number variations in schizophrenia reveal key schizophrenia susceptibility genes.

Author information

  • 1Flaum Eye Institute and Department of Ophthalmology, University of Rochester, Rochester, NY; College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China; State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China; Xiongjian_Luo@urmc.rochester.edu.
  • 2First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China; Affiliated Eye Hospital of Nanchang University, Nanchang, Jiangxi, China;
  • 3Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX;
  • 4Wuhan Institute of Virology, Chinese Academy of Sciences, WuChang, Wuhan, China;
  • 5Department of Biochemistry, Emory University, Atlanta, GA.
  • 6Flaum Eye Institute and Department of Ophthalmology, University of Rochester, Rochester, NY; College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China;

Abstract

Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics.

© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

KEYWORDS:

CHRNA7; NRXN1; copy number variation; integrative analysis; prioritization; schizophrenia

PMID:
24664977
[PubMed - in process]
PMCID:
PMC4193716
[Available on 2015-11-01]
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