Epigenetic mediation of environmental influences in major psychotic disorders

Abstract

The major psychotic disorders schizophrenia and bipolar disorder are etiologically complex involving both heritable and nonheritable factors. The absence of consistently replicated major genetic effects, together with evidence for lasting changes in gene expression after environmental exposures, is consistent with the concept that the biologic underpinnings of these disorders are epigenetic in form rather than DNA sequence based. Psychosis-associated environmental exposures, particularly at key developmental stages, may result in long-lasting epigenetic alterations that impact on the neurobiological processes involved in pathology. Although direct evidence for epigenetic dysfunction in both schizophrenia and bipolar disorder is still limited, methodological technologies in epigenomic profiling have advanced. This means that we are at the exciting stage where it is feasible to start investigating molecular modifications to DNA and histones and examine the mechanisms by which environmental factors can act upon the genome to bring about epigenetic changes in gene expression involved in the etiology of these disorders. Given the dynamic nature of the epigenetic machinery and potential reversibility of epigenetic modifications, the understanding of such mechanisms is of key relevance for clinical psychiatry and for identifying new targets for prevention and/or intervention.

Fig. 1.

The Main Components of the Epigenetic Code. The 2 main components of the epigenetic code comprise DNA methylation and histone modifications. The addition of methyl groups to CpG dinucleotides acts to repress gene activity by blocking the binding of transcription factors and attracting methyl-binding proteins. A combination of different modifications to the “tails” of histones can alter the activity of genes via structural changes to the DNA molecule.

Fig. 2.

Epigenetic Mediation of Environmental Factors During Development. Model of epigenetic mediation of environmental influences during development and the relation with the phenotypic pathway leading to major psychotic disorders. From the epigenetic perspective, environmental exposures can have long-lasting effects on gene expression and phenotype (ie, major psychotic disorders) through epigenetic mechanisms such as DNA methylation. Black circles represent epigenetic modifications to DNA (eg, methylated cytosines or histone modifications). The top row represents a nucleus of a postmitotic cells with dynamic changes to DNA modifications that may accumulate within the individual throughout development as a consequence of the synergistical combination of multiple exposures. These dynamic changes in DNA methylation may be associated with the appearance of subclinical psychotic symptoms (reflected by dashed line around the nucleus in the top row) that can become abnormally persistent and ultimately lead to the onset of a major psychotic disorder (reflected by black line around the nucleus in the top row). While this figure illustrates that major psychotic disorders are associated with accumulation of DNA modifications of a gene, scenarios are equally possible where the gene is associated with the removal of epigenetic modifications.