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Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder

Molecular Psychiatry volume 20, pages 563–572 (2015)Cite this article

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Abstract

Schizophrenia (SCZ) and bipolar disorder (BPD) are severe mental disorders with high heritability. Clinicians have long noticed the similarities of clinic symptoms between these disorders. In recent years, accumulating evidence indicates some shared genetic liabilities. However, what is shared remains elusive. In this study, we conducted whole transcriptome analysis of post-mortem brain tissues (cingulate cortex) from SCZ, BPD and control subjects, and identified differentially expressed genes in these disorders. We found 105 and 153 genes differentially expressed in SCZ and BPD, respectively. By comparing the t-test scores, we found that many of the genes differentially expressed in SCZ and BPD are concordant in their expression level (q⩽0.01, 53 genes; q⩽0.05, 213 genes; q⩽0.1, 885 genes). Using genome-wide association data from the Psychiatric Genomics Consortium, we found that these differentially and concordantly expressed genes were enriched in association signals for both SCZ (P<10−7) and BPD (P=0.029). To our knowledge, this is the first time that a substantially large number of genes show concordant expression and association for both SCZ and BPD. Pathway analyses of these genes indicated that they are involved in the lysosome, Fc gamma receptor-mediated phagocytosis, regulation of actin cytoskeleton pathways, along with several cancer pathways. Functional analyses of these genes revealed an interconnected pathway network centered on lysosomal function and the regulation of actin cytoskeleton. These pathways and their interacting network were principally confirmed by an independent transcriptome sequencing data set of the hippocampus. Dysregulation of lysosomal function and cytoskeleton remodeling has direct impacts on endocytosis, phagocytosis, exocytosis, vesicle trafficking, neuronal maturation and migration, neurite outgrowth and synaptic density and plasticity, and different aspects of these processes have been implicated in SCZ and BPD.

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Acknowledgements

This study was supported by an Independent Investigator Award from NARSAD to XC, and by National Institutes of Health Grant (R01LM011177). We thank the Stanley Medical Institute for providing the brain specimens for transcriptome sequencing. We are grateful to the PGC investigators for providing their data to the NIMH Genetics Repository. We also thank three reviewers for their valuable comments, which improved the quality of this manuscript.

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Author notes

  1. Z Zhao, J Xu and J Chen: The first three authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Biomedical Informatics and Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USA

    Z Zhao, H Yu, J Sun, Q Wang & P Jia

  2. Beijing Genomics Institute (BGI), Shenzhen, Guangdong, China

    J Xu, F Xu, Y Zhang & Z Peng

  3. Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    J Chen, M Reimers, S-A Bacanu, K S Kendler & X Chen

  4. Stanley Laboratory of Brain Research, Rockville, MD, USA

    S Kim

  5. Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA

    C Liu

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Zhao, Z., Xu, J., Chen, J. et al. Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder. Mol Psychiatry 20, 563–572 (2015). https://doi.org/10.1038/mp.2014.82

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