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Dysregulation of circRNA expression in the peripheral blood of individuals with schizophrenia and bipolar disorder

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Abstract

Circular RNAs (circRNAs) are head-to-tail back-spliced RNA transcripts that have been linked to several biological processes and their perturbation is evident in human disease, including neurological disorders. There is also emerging research suggesting circRNA expression may also be altered in psychiatric and behavioural syndromes. Here, we provide a comprehensive analysis of circRNA expression in peripheral blood mononuclear cells (PBMCs) from 39 patients with schizophrenia and bipolar disorder as well as 20 healthy individuals using deep RNA-seq. We observed systematic alternative splicing leading to a complex and diverse profile of RNA transcripts including 8762 high confidence circRNAs. More specific scrutiny of the circular transcriptome in schizophrenia and bipolar disorder, compared to a non-psychiatric control group, revealed significant dysregulation of 55 circRNAs with a bias towards downregulation. These molecules were predicted to interact with a large number of miRNAs that target genes enriched in psychiatric disorders. Further replication and cross-validation to determine the specificity of these circRNAs across broader diagnostic groups and subgroups in psychiatry will enable their potential utility as biomarkers to be established.

Key messages

• We identified 8762 high confidence circRNAs with systematic alternative splicing in human PBMCs.

• CircRNAs were dysregulated in schizophrenia and bipolar disorder, compared to a non-psychiatric control group.

• The DE circRNAs were predicted to interact with miRNAs with target genes enriched in psychiatric disorders.

• Some circRNAs have the potential to serve as biomarkers in psychiatry.

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Availability of data and material

As the sequencing data belong to patients, we cannot make them available at this stage.

Code availability

Not applicable.

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Funding

This study was supported by the New South Wales Health, Collaborative Genomics grant programme (MC, MG, VC), a NARSAD Independent Investigator Grant (MC) and National Health and Medical Research Council (NHMRC) project grants (1067137, 1147644, 1051672). MC is supported by an NHMRC Senior Research Fellowship (1121474) and a University of Newcastle Faculty of Health and Medicine Gladys M Brawn Senior Fellowship.

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Authors and Affiliations

  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia

    Ebrahim Mahmoudi & Murray J. Cairns

  2. Centre for Brain and Mental Health Research, University of Newcastle, Callaghan, NSW, 2308, Australia

    Ebrahim Mahmoudi & Murray J. Cairns

  3. Hunter Medical Research Institute, New Lambton Heights, Australia

    Ebrahim Mahmoudi & Murray J. Cairns

  4. School of Psychiatry, University of New South Wales (UNSW), Sydney, NSW, Australia

    Melissa J. Green

  5. Neuroscience Research Australia (NeuRA), Randwick, NSW, Australia

    Melissa J. Green

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  1. Ebrahim Mahmoudi
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EM was involved in the research design, methodology and data analysis, and writing the first draft. MG contributed to the study design, data interpretation and revising the manuscript. MC was involved in the supervision of the project, design of the study, interpretation of data and revising the manuscript. All authors read and approved its final version.

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Correspondence to Murray J. Cairns.

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This study was approved by the Human Research Ethics committees of the University of New South Wales (HC12384), St Vincent’s Hospital (HREC/10/SVH/9) and the South East Sydney and Illawarra Area Health Service (HREC 09/081).

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Mahmoudi, E., Green, M.J. & Cairns, M.J. Dysregulation of circRNA expression in the peripheral blood of individuals with schizophrenia and bipolar disorder. J Mol Med 99, 981–991 (2021). https://doi.org/10.1007/s00109-021-02070-6

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  • DOI: https://doi.org/10.1007/s00109-021-02070-6

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