Using high throughput technologies for the identification of genes regulated by glucocorticoid receptor (GR) and MR in brain areas responsible for specific symptoms of stress-related disorders will yield potential new drug targets for the treatment of depression and anxiety.
In this review we summarize different approaches used to alter or eliminate glucocorticoid receptor expression and function, and discuss their relevance as models for depression.
We found association between the diagnosis of depression and DNA sequence variants in intron 2 as well as in the 5' region of the NR3C1 gene but not for the previously studied exon 2 and putative promoter variants (global test after control of multiple testing, P = 0.02).
Given the role of GR-mediated negative feedback in mediating response to stress, and the clear link between stress and depression, it is plausible that polymorphisms in the GR gene (NR3C1) act to increase susceptibility.
In association studies, increased susceptibility to depression has been noted in those with polymorphisms in the following: D-amino-acid-oxidase activator/G30 gene complex, glucocorticoid receptor gene, serotonin transporter gene, tryptophan hydroxylase 2 gene, dopamine transporter gene and G protein-coupled receptor 50 gene.
In a cross-sectional genetic association study of 526 white outpatients with chronic coronary heart disease, we examined whether haplotypes of the glucocorticoid receptor gene (NR3C1) are associated with depression.
FKBP5 is a glucocorticoid receptor-regulating co-chaperone of hsp-90 and, therefore, is suggested to play a role in the regulation of the hypothalamic-pituitary-adrenocortical system and the pathophysiology of depression.
Haplotypic variation in the regulatory region of the NR3C1 may increase vulnerability to depressive disorders requiring hospital admission, but is not associated with self-reported symptoms.
Therefore, the interaction of two polymorphisms, one on the cholinergic CHRNA4 receptor gene and one on the glucocorticoid receptor gene (NR3C1), on depression was investigated.
In this study, we tested the leukocyte mRNA expression levels of genes belonging to glucocorticoid receptor (GR) function (FKBP-4, FKBP-5, and GR), inflammation (interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-7, IL-8, IL-10, macrophage inhibiting factor (MIF), and tumor necrosis factor (TNF)-α), and neuroplasticity (brain-derived neurotrophic factor (BDNF), p11 and VGF), in healthy controls (n=34) and depressed patients (n=74), before and after 8 weeks of treatment with escitalopram or nortriptyline, as part of the Genome-based Therapeutic Drugs for Depression study.
Conclusively: (1) depression in females may result from a gene × childhood-adversity interaction and/or a dysregulated epigenetic programming of MAOA; (2) childhood-adversity subtypes may differentially impact DNA methylation at NR3C1; (3) baseline MAOA-genotypic variations may affect the extent of NR3C1 methylation.
Controlling for relevant covariates, infants whose mothers reported depression during pregnancy and showed greater methylation of placental NR3C1 CpG2 had poorer self-regulation, more hypotonia, and more lethargy than infants whose mothers did not report depression.
In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.
Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders.
Methylation in CpG sites in candidate genes were not predictors of depression at significance levels corrected for whole genome testing, but maltreated and control children did have significantly different β values after Bonferroni correction at multiple methylation sites in these candidate genes (e.g., BDNF, NR3C1, FKBP5).
We investigated PTSD and depression severity, plasma cortisol, GR and mineralocorticoid receptor (MR) levels, and methylation status of NR3C1 and NR3C2 promoter regions in 25 women exposed to the Tutsi genocide during pregnancy and their children, and 25 women from the same ethnicity, pregnant during the same period but not exposed to the genocide, and their children.