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Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings

Molecular Psychiatry volume 25, pages 1718–1748 (2020)Cite this article

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Abstract

Schizophrenia and other psychotic disorders are highly debilitating psychiatric conditions that lack a clear etiology and exhibit polygenic inheritance underlain by pleiotropic genes. The prevailing explanation points to the interplay between predisposing genes and environmental exposure. Accumulated evidence suggests that epigenetic regulation of the genome may mediate dynamic gene–environment interactions at the molecular level by modulating the expression of psychiatric phenotypes through transcription factors. This systematic review summarizes the current knowledge linking schizophrenia and other psychotic disorders to epigenetics, based on PubMed and Web of Science database searches conducted according to the PRISMA guidelines. Three groups of mechanisms in case–control studies  of human tissue (i.e., postmortem brain and bio-fluids) were considered: DNA methylation, histone modifications, and non-coding miRNAs. From the initial pool of 3,204 records, 152 studies met our inclusion criteria (11,815/11,528, 233/219, and 2,091/1,827 cases/controls for each group, respectively). Many of the findings revealed associations with epigenetic modulations of genes regulating neurotransmission, neurodevelopment, and immune function, as well as differential miRNA expression (e.g., upregulated miR-34a, miR-7, and miR-181b). Overall, actual evidence moderately supports an association between epigenetics and schizophrenia and other psychotic disorders. However, heterogeneous results and cross-tissue extrapolations call for future work. Integrating epigenetics into systems biology may critically enhance research on psychosis and thus our understanding of the disorder. This may have implications for psychiatry in risk stratification, early recognition, diagnostics, precision medicine, and other interventional approaches targeting epigenetic fingerprints.

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Fig. 1: Overview of epigenetic regulatory mechanisms.

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Author notes

  1. Vinita Jagannath

    Present address: Merck Sharp & Dohme (MSD) R&D Innovation Centre, London, UK

  2. These authors have contributed equally: Lukasz Smigielski, Vinita Jagannath

Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland

    Lukasz Smigielski, Vinita Jagannath, Susanne Walitza & Edna Grünblatt

  2. The Zurich Program for Sustainable Development of Mental Health Services (ZInEP), University Hospital of Psychiatry Zurich, Zurich, Switzerland

    Lukasz Smigielski, Wulf Rössler & Susanne Walitza

  3. Department of Psychiatry, Psychotherapy and Psychosomatics, University Hospital of Psychiatry, University of Zurich, Zurich, Switzerland

    Wulf Rössler

  4. Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany

    Wulf Rössler

  5. Laboratory of Neuroscience, Institute of Psychiatry, Universidade de São Paulo, São Paulo, Brazil

    Wulf Rössler

  6. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

    Susanne Walitza & Edna Grünblatt

  7. Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

    Susanne Walitza & Edna Grünblatt

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SW has received royalties from Thieme Hogrefe, Kohlhammer, Springer, and Beltz and lecture honoraria from Opopharma in the last 5 years. Her research has been supported by the Swiss National Science Foundation (SNSF), several EU FP7s, HSM High Specialized Medicine of the Canton Zurich, Switzerland, Bfarm Germany, the Hartmann Müller Foundation, Olga Mayenfisch Foundation, and Gertrud Thalmann Foundation. Outside professional activities and interests are declared in the following link of the University of Zurich (www.uzh.ch/prof/ssl-dir/interessenbindungen/client/web/). The other authors declare no potential conflicts of interest.

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Smigielski, L., Jagannath, V., Rössler, W. et al. Epigenetic mechanisms in schizophrenia and other psychotic disorders: a systematic review of empirical human findings. Mol Psychiatry 25, 1718–1748 (2020). https://doi.org/10.1038/s41380-019-0601-3

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