Impact of DNA Methylation on Schizophrenia and Bipolar Disorders
Mental health is a public health issue. In particular, Schizophrenia (SCZ), Bipolar I and II (BD), and Autism Spectrum Disorder (ASD) are chronic disorders that will impact those diagnosed in many areas of functioning. For example, the DSM5 notes five domains of abnormalities in "Schizophrenia spectrum and other psychotic disorders: delusions, hallucinations, disorganizing thinking (speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms" (DSM5). Often, patients with mental health disorders embark on diagnostic and treatment odysseys, which impact their health and functioning and those around them. The 2022 literature review by Alameda et al. explores the impact of DNA methylation and biological pathways on six specific mental health disorders. In addition, it aims to explore the impact of environmental risk factors, specifically childhood adversity and cannabis use, on epigenetic modifications.
Although their review did not explore ethical issues, one possible ethical issue is the availability and lack of use of psychopharmacogenetics prior to the prescription of medical treatment for mental health disorders. Patients are often prescribed typical medications in a one size fits all approach and instructed to try them for a few weeks. However, if psychopharmacogenetic testing was more widely used, prescribed medications could be targeted to provide more efficient symptom relief and decrease the time patients spend on a medication odyssey. In addition, understanding the biological pathways in these mental health disorders could lead to more efficient and effective treatment of these disorders.
The authors examine the evidence of epigenetic processes in six pathways, serotoninergic pathway, dopaminergic pathway, glutamatergic/GABAergic pathway, synaptic plasticity and neurogenesis, immune system and inflammation, and oxidative stress. In addition, they examine the impact of childhood adversity and cannabis use on epigenetics. This paper will explore many of the pathways explored by the authors. The primary epigenetic process examined by the authors is DNA methylation which they abbreviate as DNAm and define as "the covalent addition of a methyl group to the 5th carbon of a Cytosine (C) base, resulting in a 5-methylcytosine (5-mC) base" (Alameda et al., 2022).
Serotoninergic Pathway
Serotonin system dysfunction is linked to many psychiatric disorders. Four studies have demonstrated increased methylation of "the serotonin translated genes (mainly SLC6A4)" in Major Depressive Disorder and Bipolar Disorder (Alameda et al., 2022). In addition, the differential DNA methylation of 5-HTR1A, 5-HTR2A, HTR2A, HTR5A, and HTR1E are found in Schizophrenia, Bipolar Disorder, and psychosis. Furthermore, the MAO-A gene is associated with hypomethylation in Anxiety Disorders, specifically acrophobia or "abnormal fear of heights" and Obsessive Compulsive Disorder (Misiewicz et al., 2016). In addition, increased methylation of the MAO-A gene is linked to improved therapeutic responses in Anxiety Disorders.
Dopaminergic Pathway
Dysfunctional regulation of dopamine is currently the best and most studied cause of Schizophrenia. Atypical or abnormal DNA methylation levels in DRD3 and DRD4 genes have been linked to Schizophrenia. In addition, hypomethylation of COMT, SLC6A3, and FAM63B have also been identified in individuals with Schizophrenia. These genes involve dopamine expression, COMT and FAM63B, or dopamine transport, SLC6A3.
Glutamatergic/GABAergic Pathway
Abnormal DNA methylation of Parvalbumin (PVALB), GMR2/GMR5, and GABRB2 are linked with Schizophrenia and psychosis. These genes function in excitatory/inhibitory balance, glutamine reception, and GABA reception. In addition, loci involved in glutamine and GABA neurotransmission demonstrated abnormal levels of DNA methylation and post-mortem brains of those with Schizophrenia and Bipolar disorder. The authors found less compelling evidence of a link between this pathway and Autism and Major Depressive Disorder. A larger number of hyperacetylated sites on GABA receptor genes was linked to Autism Spectrum Disorder. In regards to depression, "115 differently methylated regions" were found in the "post-mortem brains of suicide victims" (Alameda et al., 2022).
Synaptic Plasticity and Neurogenesis
DNA methylation of neurotrophic factors has been linked to "Schizophrenia, Bipolar disorders, Post-traumatic Stress Disorder. Depression, Borderline Personality Disorder, Anxiety Disorders, Eating Disorders, and Autism Spectrum Disorders" (Alameda et al., 2022). The brain-derived neurotrophic factor (BDNF) provides an important epigenetic marker for these mental health disorders.
Immune System and Inflammation
Regions and genes linked to inflammatory regulation, cytokine secretion, immune system enrichment, and T-cell development have been linked to DNA methylation in Schizophrenia, depression, Post-traumatic Stress Disorder, Autism, and Panic Disorder.
Oxidative Stress
Although there is not much evidence, there was a small link between methylation levels of oxidative stress regulation genes in Borderline Personality Disorder. Overall, "oxidative stress has been shown to play a role in epigenetic modifications, enhancing inflammatory gene transcription" (Alameda et al., 2022)
Childhood Adversity
Overall there is an association between childhood adversity (CA), mental health disorders, and some genes of the serotonin, glutamine, and neurogenesis pathways. Therefore, the authors suggest that childhood adversity could account for some of the DNA methylations in these disorders. For example, there is a correlation between the experience of childhood adversity and DNA methylation in Borderline Personality Disorder and Major Depressive Disorder (MDD). This correlation involves the hypothalamus pituitary adrenal pathway (HPA). In addition, "hypermethylation of SLC6A has been linked to exposure to CA and associated with the worst clinical presentation in MDD" (Alameda et al., 2022).
Childhood adversity and DNA methylation changes are linked to genes involved in inflammatory and neurogenesis pathways. For example, the" TNFRSF13C gene was differently methylated between Borderline PD participants with and without CA" (Alameda et al., 2022). Additionally, in patients with Bipolar Disorder (BD) and Borderline Personality Disorder who experience childhood adversity, DNA methylation changes were observed in genes associated with the creation of myelin and the formation of neurons. Borderline Personality Disorder patients had different levels of DNA methylation of the CGTC gene depending on their experience of childhood adversity.
Cannabis Use
Heavy cannabis use is associated with DNA methylation changes in dopamine transmission genes, specifically DRD2, DAT1, and COMT. In addition, a significant difference in CpG site methylation of the CEMIPG gene was reported with lifetime cannabis use. "The CEMIP gene … which has been shown to have an important role in inflammation, immune processes as well as associated with BD & SCZ previously" (Alameda et al., 2022). In addition, there appear to be epigenetic differences between individuals who use cannabis alone and those who use cannabis and tobacco.
Conclusion
The authors note the need for further and more extensive studies in this area. In addition, they cite the importance of collaboration, especially given the variety of environmental factors. Finally, given the interplay between multiple pathways underlying mental health disorders, the authors suggest using "phenotypic characterizations "or observable behaviors and traits rather than psychiatric diagnoses (Alameda et al., 2022).
References:
Alameda, L., Trotta, G., Quigley, H., Rodriguez, V., Gadelrab, R., Dwir, D., Dempster, E., Wong, C., & Forti, M. D. (2022). Can epigenetics shine a light on the biological pathways underlying major mental disorders?. Psychological medicine, 52(9), 1645–1665. https://doi.org/10.1017/S0033291721005559
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). https://doi.org/10.1176/appi.books.9780890425596
Misiewicz, Z., Hiekkalinna, T., Paunio, T., Varilo, T., Terwilliger, J. D., Partonen, T., & Hovatta, I. (2016). A genome-wide screen for acrophobia susceptibility loci in a Finnish isolate. Scientific reports, 6, 39345. https://doi.org/10.1038/srep39345