Mineralocorticoid receptor gene variants as determinants of HPA axis regulation and behavior.

We tested if common mineralocorticoid receptor (MR) gene variants contribute to the variability in neuroendocrine control and behavioral reactivity as observed in humans. For that purpose we screened for genetic variability and tested functionality of the identified human MR gene variants in vitro. Four haplotypes were tested for transactivational capacity in vitro and showed profound significant differences when stimulated with cortisol. The MR gene variants were associated with basal levels of cortisol, cortisol levels after dexamethasone administration and with stress-induced hypothalamic-pituitary-adrenal axis and autonomic reactivity. In an elderly cohort, one of the functional MR gene variants, MR-I180V, associated with higher feelings of depression. Moreover, we found an association with neuroticism in a second cohort consisting of depressed patients. In conclusion, we report here new findings on common functional human MR gene variants which reveal a hitherto unknown role of these variants in neuroticism conferring vulnerability to stress-related mental disorders, such as depression and posttraumatic stress syndrome.