Can epigenetics shine a light on the biological pathways underlying major mental disorders?

Abstract

A significant proportion of the global burden of disease can be attributed to mental illness. Despite important advances in identifying risk factors for mental health conditions, the biological processing underlying causal pathways to disease onset remain poorly understood. This represents a limitation to implement effective prevention and the development of novel pharmacological treatments. Epigenetic mechanisms have emerged as mediators of environmental and genetic risk factors which might play a role in disease onset, including childhood adversity (CA) and cannabis use (CU). Particularly, human research exploring DNA methylation has provided new and promising insights into the role of biological pathways implicated in the aetio-pathogenesis of psychiatric conditions, including: monoaminergic (Serotonin and Dopamine), GABAergic, glutamatergic, neurogenesis, inflammatory and immune response and oxidative stress. While these epigenetic changes have been often studied as disease-specific, similarly to the investigation of environmental risk factors, they are often transdiagnostic. Therefore, we aim to review the existing literature on DNA methylation from human studies of psychiatric diseases (i) to identify epigenetic modifications mapping onto biological pathways either transdiagnostically or specifically related to psychiatric diseases such as Eating Disorders, Post-traumatic Stress Disorder, Bipolar and Psychotic Disorder, Depression, Autism Spectrum Disorder and Anxiety Disorder, and (ii) to investigate a convergence between some of these epigenetic modifications and the exposure to known risk factors for psychiatric disorders such as CA and CU, as well as to other epigenetic confounders in psychiatry research.

Keywords: DNA-methylation; Epigenetics; childhood trauma; mental health disorders.

Fig. 1.

Summary of the evidence on potential pathways linking childhood trauma and cannabis use with psychiatric conditions through DNAm changes. Note: This figure summarises the evidence presented in this review, highlighting the idea that some biological pathways linking environmental risk factors with mental health disorders via epigenetic changed in the form of DNAm are transdiagnostics (e.g immune system/inflammation) while others seem to be more specific (e.g dopaminergic system). (1) The environmental risk factors row and epigenetic modifications row suggest links between childhood adversity (CA), and Cannabis use (CU) and DNAm changes mapping to biological pathways which are also functionally related (Serotoninergic, Dopaminergic pathways, Glutamatergic & GABAergic pathway, Neurogenesis, Immune system & Inflammation and Oxidative stress). (2)The epigenetic modifications row and mental health disorders row illustrate the evidence, from case–control studies, of an association between DNAm changes in these pathways and the major mental health conditions (Eating Disorders (anorexia nervosa and bulimia nervosa) Post-traumatic stress disorder, Anxiety Disorders, Psychotic Disorder, Bipolar disorders, Depression and Autism Spectrum Disorders). (3) The arrows connecting the three rows show the potential mediating role of DNAm changes linking CA and CU and risk to develop mental health conditions. The thickness of the lines shows the robustness of the evidence reported in the literature review. The items “genotype: and “other risk factors” are added to highlight the influence of genetic factors and environmental confounders in DNAm studies. The dotted line connecting eating disorders with the pathways indicate that literature was limited and mixed not allowing to draw clear links with the pathways.

Fig. 2.

Summary of the evidence linking childhood adversity and DNAm changes on the Hipotalamic Pituitary Adrenal Axis in various conditions as well as with some clinical measures. Note: This Figure illustrates the evidence from candidate gene studies linking childhood adversity (CA) with DNAm in CpG sites located in NR3C1, FKBP5, SKA2 and CA, with various conditions and various clinical outcomes. In the gene and DNAm columns, CA + (with an arrow pointing up) reflects the presence of a positive association between the DNAm in probes located in those genes and CA; CA- (with an arrow pointing down) reflects a negative association. The disorder column shows in which mental health condition that association has been found. Lastly, the clinical outcomes column shows the presence of evidence linking DNAm, with a particular clinical phenotype; CA + indicated that the association between DNAm and the clinical outcome was related to CA.