Cytosine methylation of NR3C1 has been repeatedly associated with trauma and mental disorders, including major depression, post-traumatic stress disorder, anxiety, and personality disorders, suggesting that NR3C1 methylation may play a role in stress-related psychopathology.
Methylation at the exon 1<sub>F</sub> of the glucocorticoid receptor gene NR3C1 has been associated with both early stress exposure and risk for developing a psychiatric disorder; however, other NR3C1 promoter regions have been underexplored.
In the context of environmental stress, a functional variant in the glucocorticoid receptor co-chaperone FKBP5 gene has been repeatedly shown to increase risk for psychiatric illness, including depression.
The glucocorticoid receptor (GR) isoform α plays an important role in the negative feedback regulation of the HPA axis and reduced GRα messenger RNA (mRNA) expression has been shown in mood disorder patients and first-degree relatives compared to healthy individuals with no family history of psychiatric disorders.
We present recent evidence related to epigenetic regulation of genes involved in hypothalamus-pituitary-adrenal axis regulation, namely, the glucocorticoid receptor gene (nuclear receptor subfamily 3, group C, member 1 [NR3C1]) and FK506 binding protein 51 gene (FKBP5), after childhood adversity and associations with risk for psychiatric disorders.
FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity.
Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain.
The specific psychopathology an individual might develop in the aftermath of stressful events can be highly variable, however, most studies investigating hGR methylation and psychopathology suffer from being limited to a single symptom cluster of mental disorders.
Differential effects of maternal and paternal posttraumatic stress disorder (PTSD) have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder.
The FKBP5 gene product regulates glucocorticoid receptor (GR) sensitivity and hypothalamic-pituitary-adrenal axis functioning and has been associated with many stress-related psychiatric disorders.
Altered glucocorticoid receptor (GR) mRNA and protein expression in the dorsolateral prefrontal cortex (DLPFC) in psychiatric illness have also been reported, but the cause of these abnormalities is not known.
These findings reveal selective abnormalities of GR mRNA expression in the lateral OFC in psychiatric illness, which are more specific and may be less influenced by NR3C1 genotype than those of the dorsolateral prefrontal cortex reported previously.