Epigenetics as a link between psychosocial factors and mental disorders.

Previously, based on animal studies (mice and rats), I had suggested that psychosocial factors are involved in the pathogenesis of mental disorders by acting via mechanisms involving epigenetics (heritable changes in gene expression without changes in DNA sequence).[1] Epigenetic mechanisms include DNA methylation and modifications of histones (DNA packaging proteins). Based on human studies, I here provide further evidence that psychosocial factors act via epigenetic mechanisms in the pathogenesis of mental disorders, and suggest that epigenetics is a link between psychosocial factors and mental disorders.

McGowan et al.[2] found that in postmortem hippocampus from suicide victims with a history of childhood neglect/abuse, the gene encoding ribosomal RNA (rRNA) was significantly hypermethylated throughout the promoter and the 5’regulatory region compared to that of control subjects who died suddenly of unrelated causes without a history of childhood abuse/neglect, consistent with reduced rRNA expression in the hypothalamus. Most of the study subjects they included had a history of mental disorder. They later examined epigenetic differences in a glucocorticoid receptor (GR) gene promoter between postmortem hippocampus from suicide victims with a history of childhood neglect/abuse and that from either suicide victims with no such history or controls who had experienced sudden accidental death.[3] They found there were decreased levels of GR gene messenger RNA, and increased DNA methylation of the GR gene promoter in suicide victims with a history of childhood neglect/abuse compared to suicide victims with no such history and control subjects who experienced sudden accidental death. Most of the suicide victims they included had a history of mental disorder. Hence, McGowan et al. suggested that childhood neglect/abuse could have acted epigenetically to contribute to suicide. Beach et al.[4] showed that DNA methylation of the promoter of the gene encoding the serotonin transporter (5-HTT) mediated the impact of child sex abuse on women's antisocial behaviour when they were adults. They studied DNA methylation in cell lines of lymphoblasts obtained from the study subjects, after controlling for direct effects of biological parent psychopathology and 5-HTT genotype. More recently, Smith et al.[5] evaluated African American subjects matched by age and sex, and stratified into four groups by posttraumatic stress disorder (PTSD) diagnosis, and history of child abuse. Total life stress (TLS) was also assessed in all subjects. DNA obtained from peripheral blood was assessed for global and site-specific methylation. DNA methylation levels were examined for association with PTSD, history of child abuse, and TLS, after adjusting for age, sex, and experimental effects. They found that global DNA methylation was raised in subjects with PTSD. DNA in five genes was differentially methylated in subjects with PTSD. Many of these genes have been previously associated with inflammation. In further studies, they found that plasma levels of interleukin-4 (IL-4), IL-2 and tumor necrosis factor-alpha correlated with PTSD, child abuse, and TLS, suggesting to them that psychosocial stress alters global and gene-specific DNA methylation patterns potentially associated with immune dysregulation.