Genetic determinants of cortisol responses to daily life stressors

Abstract

Introduction: Studies consistently link stress with an increased risk for major depression (MD). The underlying causality proposes a dysfunctional regulation of the neuroendocrine stress response, in particular the hypothalamic-pituitary-adrenal-axis (HPA-axis). However, the link between HPA-axis dysfunction and MD is not completely straightforward since not all individuals succumb to depressional onset after experiencing stressful events. Epidemiologic studies explain this variance by showing that MD is subject to specific gene-environment interactions, providing each individual a unique reactivity to experienced stressful life events (SLEs). This imposes the search for genetic variations at the basis of HPA-axis regulation, rendering some individuals more susceptible to MD onset after experiencing SLEs. To overcome methodological difficulties often encountered in genetic association studies, our study examined the influence of genetic variations on individual stress sensitivity, a previously described endophenotype of depression. Genetic mutations found in the serotonergic system (5-HT1AC-1019-G, MAO-A uVNTR) were primarily studied, since this system is a principal regulator of the HPA-axis. It is hypothesized that genetic determinants, which have previously been associated with a higher risk for MD, will influence HPAaxis reactivity providing individual variability in stress sensitivity and MD risk. Materials and Methods: Participants were recruited from the East Flanders Prospective Twin Survey (EFPTS), a longitudinal female twin population used to investigate gene-environment interactions in affective disorders. From this population, saliva samples for cortisol measures were collected in conjunction with registration of minor daily life stressors. To assess the effects of these stressors, the experience sampling method (ESM) was used. ESM measures fluctuations in three different daily life stressors: social, activity- and event-related stress. The influence of genetic variations on salivary cortisol levels in response stressors was examined by multilevel regression analysis. Results: Social stress, but not activity- and event-related stress, significantly elevated salivary cortisol levels. Moreover, there was a significant association between the 5-HT1A genotype and diurnal cortisol variations. Also, a significant elevation in social stress-induced cortisol levels was observed in function of 5-HT1A genotype. In contrast to 5-HT1A genotype, no significant association between the MAO-A genotype and HPA-axis reactivity after experiencing minor daily life stressors was found. Conclusion: Social stressors appear to be essential predictors of cortisol response to minor daily life stressors in our female population. Additionally, our findings link a polymorphism in the 5-HT1A gene with an increased sensitivity and responsiveness of the HPA-axis to daily life stressors. This association could not be found for variations in the MAOA gene, another important regulator of the serotonergic system. These data suggest that 5-HT1A receptors play a primary role in serotonergic regulation of HPA-axis reactivity to minor daily life stressors. In addition, these data further support the use of reliable endophenotypes for analyzing the contribution of genetic variations to the development of psychiatric disorders like MD.