A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females

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.

A Stress-Induced Shift From Trace to Delay Conditioning Depends on the Mineralocorticoid Receptor

“…However, if our findings hold in patient samples, we suggest that the shift is dependent on MR-activation and might be prevented by short-term administration of MR antagonists. Related to this suggestion, more recent studies associated genetic variants in the gene encoding the MR with interindividual differences in risk for psychopathology (69)(70)(71)(72). Our findings could have mechanistic implications for understanding of the impact of stress on daily life and mental wellbeing, which might be particularly prominent in individuals with high MR sensitivity.…”

Mineralocorticoid Receptor Stimulation Improves Cognitive Function and Decreases Cortisol Secretion in Depressed Patients and Healthy Individuals

“…Indeed, it has been repeatedly shown that depressed patients exhibit decreased MR expression in hippocampus and prefrontal cortex in post-mortem studies (Klok et al, 2011a;Medina et al, 2013;Qi et al, 2013). Furthermore, polymorphisms and haplotypes of the MR gene have been shown to be associated with depression (Klok et al, 2011b) and to moderate the association between childhood neglect and amygdala reactivity (Bogdan et al, 2012). Also, there was an attenuated cortisol inhibition in psychotic major depression after fludrocortisone also consistent with impaired MR function in these patients (Juruena et al, 2013;Lembke et al, 2013).…”

Genetic variants in glucocorticoid and mineralocorticoid receptors are associated with concentrations of plasma cortisol, muscle glycogen content, and meat quality traits in male Nellore cattle

“…Four NR3C1 gene SNP (ER22/23EK, N363S, BclI C/G, and A3669G) and 2 NR3C2 gene SNP (À2 G/C and MR I180V) have been described to influence the transactivation ability of their receptors, resulting in changes in sensitivity to glucocorticoids, including cortisol [18,19]. Importantly, the same genetic variants in the NR3C1 gene were associated with bone mineral density, body mass index, abdominal obesity, and total cholesterol under nonstress conditions [16].…”