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.

Epigenetic Mechanism of Early Life Stress-Induced Depression: Focus on the Neurotransmitter Systems

“…One of the closely related and persistent histone modifications in ELS is a histone deacetylase (HDAC)-mediated histone acetylation ( Levine et al, 2012 ; Valzania et al, 2017 ; Shepard et al, 2018 ). Histone acetylation, the most reported histone modification in neurological diseases, is dynamically regulated by two distinct types of enzymes, histone acetyltransferases (HATs) and HDACs ( Marmorstein and Zhou, 2014 ; Alameda et al, 2022 ). HAT transferred acetyl groups to histone tails, leading to chromatin relaxation and subsequent increase in transcription rate; the latter increased chromatin-histone interactions by removing acetyl groups and ultimately decreased transcription rate ( Shepard and Nugent, 2020 ).…”

“…In addition, exposure to ELS interferes with the function and innervation of serotonergic and dopaminergic neurons in the prefrontal-limbic system neural circuit ( Gos et al, 2006 ; Jezierski et al, 2007 ; Kunzler et al, 2015 ). Multiple sources of evidence support the regulatory roles of the serotonergic system, the dopaminergic system and other neurotransmitter systems in the pathogenesis of depression ( Gershon et al, 2007 ; van der Doelen et al, 2015 ; Wang et al, 2017 ; Marrocco et al, 2019 ; Alameda et al, 2022 ). Most of the current commonly used antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, and monoamine oxidase inhibitors, primarily target monoamine neurotransmitter function ( Harmer et al, 2017 ).…”

“…Epigenetics refers to potentially heritable but environmentally modifiable changes in gene expression mediated by non-DNA-encoded mechanisms ( Sun et al, 2013 ; Park et al, 2019 ). These modifications, including DNA methylation, histone modification, and non-coding RNA, may result in the following changes in genetic transcription, synaptic plasticity, and behavior ( Tesone-Coelho et al, 2015 ; Palmisano and Pandey, 2017 ; Alameda et al, 2022 ). By nature, epigenetic mechanisms are dynamic and reversible, and they can be used as a new intervention strategy to treat psychiatric disorders ( Lesch, 2011 ).…”

“…Stress and depression are primarily associated with epigenetic alterations in genes involved in regulating resilience and/or susceptibility to stress, including stress response-related genes ( crf ) and genes involved in neurotransmission ( SLC6A4 ) ( Park et al, 2019 ). In recent years, many studies have focused on the role of epigenetics on depression-like outcomes produced by different types of ELS ( Ptak and Petronis, 2010 ; Alameda et al, 2022 ). Among various epigenetic modifications, cytosine-phosphate-guanine (CpG) methylation has the longest duration ( Guo et al, 2011 ).…”

Clinical Value of Inflammatory and Neurotrophic Biomarkers in Bipolar Disorder: A Systematic Review and Meta-Analysis

“…Regarding the identification of genetic markers for BD, a candidate gene strategy has been largely unsuccessful [ 59 ]. BDNF is one of the most investigated candidate genes by studies looking at genetic (GWAS) and epigenetic (DNA methylation and EWAS) variations associated with the risk of BD [ 60 , 61 ]. Evidence from longitudinal analysis of methylation profiles support a role of inflammatory factors (e.g., BDNF, IL-1β) in the pathogenesis of BD [ 60 ].…”