Abstract
Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.
Highlights
A fundamental question in mental health research is why some individuals can cope with stress while others can’t and become vulnerable for depression
We identified two single-nucleotide polymorphisms (SNPs) located in exon 2 of the MR (NR3C2) gene (À2G/ C and I180V; Figure 1a) that influence MR translation and/or its capacity to transactivate target genes in cell lines. These two SNPs caused differential neuroendocrine and sympathetic responses to psychological stressors.[10,11]. These SNPs were associated with differences in the cortisol awakening response, depending on an interaction with selective serotonin reuptake inhibitors or after dexamethasone treatment.[12,13]
Reconstruction of MR haplotypes resulted in one haplotype bin that was highly linked to the previously described MR -2G/C and I180V SNPs
Summary
A fundamental question in mental health research is why some individuals can cope with stress while others can’t and become vulnerable for depression. We identified two single-nucleotide polymorphisms (SNPs) located in exon 2 of the MR (NR3C2) gene (À2G/ C and I180V; Figure 1a) that influence MR translation and/or its capacity to transactivate target genes in cell lines. These two SNPs caused differential neuroendocrine and sympathetic responses to psychological stressors.[10,11] In addition, these SNPs were associated with differences in the cortisol awakening response, depending on an interaction with selective serotonin reuptake inhibitors or after dexamethasone treatment.[12,13] Most of the associations found with the MR SNPs were sex-dependent. We discovered that MR haplotype 2 enhances resilience to depression, in women and have replicated this finding in three independent studies, including data from a genome-wide association study
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