Genetic variants within the dopaminergic system interact to modulate endocrine stress reactivity and recovery

Catecholamines modulate endocrine stress reactivity by affecting regulatory influences of extra-hypothalamic brain structures on hypothalamus–pituitary–adrenal (HPA)-axis. Therefore, we aimed to investigate combined effects of functional allelic variations that affect dopamine availability in both cortical (COMT Val158Met polymorphism) and subcortical (DAT1 VNTR) brain regions on HPA-axis reactivity to psychosocial stress. By using a standardized laboratory stress task (public speaking) we obtained saliva cortisol samples during stress exposure and an extended recovery period in 100 healthy male adults. We report for the first time significant epistasis between COMT Val158Met and DAT1 VNTR on cortisol response patterns. Subjects homozygous for both the Met158 and the 10-repeat allele of DAT1 VNTR were characterized by markedly elevated cortisol reactivity and impaired stress recovery compared to all other groups. Our results indicate a crucial role of functional genetic variants within the dopaminergic system in the modulation of HPA-axis response patterns and highlight the need to investigate combined effects of specific candidate genes on stress-related endophenotypes.

Research highlights▶ We found significant epistasis between COMT Val158Met and DAT1 VNTR on cortisol response patterns during a standardized laboratory stress task. ▶ Subjects homozygous for both the Met158 and the 10-repeat allele of DAT1 VNTR demonstrate markedly elevated cortisol reactivity and impaired stress recovery. ▶ Since altered endocrine stress reactivity confers potential vulnerability for the development of stress-related disorders, our findings contribute to the understanding of biological mechanisms underlying these disorders.