Schizophrenia is a psychiatric syndrome characterized by psychotic symptoms of hallucinations,
delusions and disorganized speech, by negative symptoms such as decreased motivation and diminished
expressiveness, and by cognitive deficits. There is wide variation in the ability of persons with
schizophrenia to function in their daily lives, with some being severely disabled and others able to
function at a high level (Marder 2019). Persons with schizophrenia have lower gray-matter volumes on
magnetic resonance imaging than age-matched controls and fewer dendrites and dendritic spines in
postmortem studies. These structural features are hypothesized to contribute to altered
physiological activity and functional connectivity among the prefrontal cortex, temporal cortex,
thalamus, hippocampus, and cerebellum (Marder 2019). There have been also reports of numerous
biochemical changes in schizophrenia indicative of neurotransmitter dysfunction in multiple systems,
among the most prominent being dopamine, glutamate, serotonin, and γ-aminobutyric acid (GABA) (Gill
The underlying causes of schizophrenia include environmental and genetic factors, pointing to a
multifarious etiology. The prevailing explanation is based on the interplay between predisposing
genes and environmental exposures (Smigielski et al., 2019). Heritable factors are estimated to
explain 80% of the risk of schizophrenia in a population. However, only a small portion of this
heritable component has been shown to be attributable to common disease associated single-nucleotide
variants, or to larger but rare mutations.
Genome research has revealed that epigenetics is an additional layer
of regulation of genes and gene-associated proteins (Smigielski et al., 2019). Epigenetics refers to
the changes in gene function that are heritable but do not entail a change in DNA sequence (Dupont
et al., 2009), and encompasses heritable alterations in chromatin function and structure. Epigenetic
mechanisms also regulate important brain-related functions, such as neurogenesis, neurodegeneration,
neuronal activity, and cognition (Smigielski et al., 2019).
Accumulated evidence suggests that epigenetic regulation of genome may mediate dynamic
gene–environment interactions at the molecular level by modulating the expression of psychiatric
phenotypes through transcription factors (Smigielski et al., 2019). The dynamic and interactive
nature of epigenetics may thus contribute to the multi-level etiology of most psychiatric conditions
(Smigielski et al., 2019). These characteristics of epigenetics raise the possibility that
epigenetic defects may be corrected through different interventions including pharmacological
treatments. (Swathy et al., 2017). In fact, several antipsychotics have been found to influence
epigenetic signaling (Smigielski et al., 2019).
DNA methylation, post-translational histone modification, and RNA interference, particularly through
micro- RNAs (miRNAs), are three epigenetic mechanisms.
DNA methylation, the most documented epigenetic mechanism, is a crucial regulator of gene expression
and gene silencing, mainly by blocking the binding of transcription factors at gene promoters and by
altering chromatin structure. At present, there are varying levels of evidence in schizophrenia for
the altered DNA methylation status of genes regulating dopamine, serotonin, γ-aminobutyric acid, and
neurotrophin availability, as well as for a few genes with less understood functions (Smigielski et
al., 2019). Alelú-Paz et al. analyzed the epigenome in several brain regions from schizophrenic
patients with severe cognitive impairment and found different DNA methylation signatures depending
on the brain area analyzed (Alelú-Paz et al., 2016). Aberg et al. conducted a methylome-wide
association study of schizophrenia identifying blood biomarker signatures of environmental insults.
Their results demonstrated how methylation studies can yield biomarkers that can be used to
potentially improve disease management (Aberg et al., 2015).
Histone modifications, referring to modifications to the proteins that package and order DNA into
nucleosomes, may be transcriptionally permissive or repressive (Smigielski et al., 2019). To date,
very little is known about the histone modifications in the context of schizophrenia. Several lines
of evidence suggest that histone modifications in specific candidate genes may contribute to the
pathogenesis of prefrontal dysfunction. (Swathy et al. 2017).
The third epigenetic category involves miRNAs, which are a kind of non-coding RNAs that engage in
post-transcriptional repression or messenger RNA destabilization of many targeted genes. The
existing data generally support the hypothesis that miRNA is dysregulated in schizophrenia and other
psychotic disorders (Smigielski et al., 2019). It has been shown that the genetically based
dysregulation of miRNAs undermines miRNA inhibitory effects, resulting in the abnormal upregulation
of genome transcription contributing to the development of schizophrenia (Zhang et al., 2015).
The recent understandings in epigenetics on schizophrenia has provided deeper insights in
identifying epigenetic patterns of histone modifications, methylations and miRNAs in the
pathogenesis of the disease. Accumulative evidence suggests that antipsychotic drugs can also alter
the epigenetic homeostasis. Thus, the emerging field of pharmacoepigenomics is providing promising
insights into the role of drugs in modulating host epigenome, as well as in addressing
interindividual variability in drug response and drug-related adverse effects (Swathy et al., 2017).
Aberg KA, McClay JL, Nerella S, et al. Methylome-wide association study of schizophrenia:
identifying blood biomarker signatures of environmental insults. JAMA Psychiatry,
Alelú-Paz R, Carmona FJ, Sanchez-Mut JV, et al. Epigenetics in Schizophrenia: A Pilot Study of
Global DNA Methylation in Different Brain Regions Associated with Higher Cognitive Functions.
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Gill K, Grace A. The role of neurotransmitters in schizophrenia. In: Schizophrenia and Psychotic
Spectrum Disorders. Oxford University Press; 2016. p.153–84
Stephen R. Marder and Tyrone D. Cannon. Schizophrenia. N Engl J Med. 2019 Oct
Montano C, Taub MA, Jaffe A, et al. Association of DNA Methylation Differences With
Schizophrenia in an Epigenome-Wide Association Study. JAMA Psychiatry, 2016;73(5):506–514.
Smigielski L, Jagannath V, Rössler W, Walitza S, Grünblatt E. Epigenetic mechanisms in
schizophrenia and other psychotic disorders: a systematic review of empirical human findings.
Mol Psychiatry. 2020 Jan 6 [Epub ahead of print].
Swathy B, Banerjee M. Understanding epigenetics of schizophrenia in the backdrop of its
antipsychotic drug therapy. Epigenomics, 2017;9(5):721–736.
Zhang F, Xu Y, Shugart YY, et al. Converging evidence implicates the abnormal microRNA system in
schizophrenia. Schizophr Bull.,2015;41(3):728–735.