Unipolar depression and hippocampal volume: Impact of DNA sequence variants of the glucocorticoid receptor gene

Abstract

Glucocorticoid receptor (GR) plays a major role in regulation of the hypothalamic-pituitary-adrenocortical (HPA) system; HPA dysregulation represents the most consistent biological pattern of depression. Multiple functional polymorphisms are known for the GR gene, which might influence the development of unipolar depression. Previous studies reported associations to some variants in this gene but not consistently so. We investigated seven genetic polymorphisms in the GR gene (NR3C1) located in the putative promoter, exon 2 and intron 2 region. Study populations were 322 German inpatients with recurrent unipolar depression, and 298 German controls recruited from the general population. The relationships between intermediate phenotypes (hippocampal and amygdala volumes) and NR3C1 DNA sequence variants were additionally explored in a subpopulation of patients. 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). In patients, diagnosis-related alleles were also associated to hippocampal volume reduction and amygdala volume variation. Unipolar depression is associated with DNA variants of the NR3C1 gene in our population. Neurobiological underpinnings of depression as volumetric reductions of the hippocampus may also be mediated by variants in this gene.

Maternal Depression and Child and Adolescent Depression Symptoms: An Exploratory Test for Moderation by CRHR1, FKBP5 and NR3C1 Gene Variants

“…However, similar to our findings, one previous study failed to detect significant G 9 E between the same variants in the CRHR1 gene and child abuse when utilising a different measure which unlike the one used by Bradley and colleagues, was not reliant on the recall of emotional memories (Polanczyk et al 2009). This suggests that the individual recall of negative emotions in relation to stressors or the exact type of measure might be important when investigating G 9 E. The adversity measure (recurrent maternal depression) in the present study is not based on the child's perception or emotional recall of family experiences, it is purely an assessment of exposure versus Bradley et al 2008;van Rossum et al 2006;Zobel et al 2008) Gene and SNP accession number non-exposure. It may also be the case that the construct of exposure to recurrent maternal depression needs to be disaggregated into more proximal environmental risk components such as negative family relationships (Pilowsky et al 2008) or ''current'' exposure.…”

“…Individuals with the Bcl1 polymorphism have been found to show an increased sensitivity to glucocorticoids in response to the dexamethasone suppression test (van Rossum et al 2006). The Bcl1 polymorphism has also been found to occur more frequently in groups of depressed cases versus controls (van Rossum et al 2006;Zobel et al 2008). These results suggest that individuals carrying these variants might be at risk of displaying chronically elevated stress hormone levels which may constitute a risk factor for stress-related disorders including depression.…”

“…G 9 E was weakest in relation to stressful life events although interview assessments of life events appeared to be superior to questionnaires. Bradley et al 2008;van Rossum et al 2006;Zobel et al 2008) Gene and SNP accession number Mean, SD, child/adolescent depression scores In addition to variants in the CRHR1 gene which have previously been found to interact with stress exposure to predict depression, a secondary aim was to investigate several other polymorphisms linked to depression. G 9 E between maternal depression and three polymorphisms in the FKBP5 gene which is known to regulate the function of the glucocorticoid receptor were investigated along with a known polymorphism in the glucocorticoid receptor gene.…”

Brain volume abnormalities in major depressive disorder: A meta‐analysis of magnetic resonance imaging studies

“…Especially functional polymorphisms of the NR3C1 gene (Nuclear Receptor Subfamily 3, Group C, Member 1) are associated with increased susceptibility to MDD [van Rossum et al, 2006;van West et al, 2006]. Of particular interest are the findings of a recent study reporting an association of four illness-related polymorphisms of the NR3C1 gene with overall smaller hippocampal volumes in patients with MDD [Zobel et al, 2008]. This suggests that ''at-risk''-alleles of the NR3C1 gene influence hippocampal volume.…”

Single Nucleotide Polymorphisms Related to HPA Axis Reactivity

“…However, which GR gene SNPs contribute to this effect is unclear, although it indicates involvement of the GR with basal cortisol regulation. In the promoter region of the GR gene, between exon 1A 1-3 and exon 1D, in a large intron of approximately 27 kb, the TthIII I restriction site (rs100529570) is located [77,78] . No in vitro testing for this TthIII I restriction site has been reported.…”