Many studies have found that hypothalamic–pituitary–adrenal (HPA) axis abnormalities are related to the pathophysiology of major depressive disorder (MDD) and cognitive functioning. Our aim was to assess the influence of genetic polymorphisms and methylation levels in three different promoter regions throughout the glucocorticoid receptor (GR) gene NR3C1 on cognitive performance in MDD. Plausible interactions with childhood adversity and mediation relationships between genetic and epigenetic variables were explored.

The sample included a total of 64 MDD patients and 82 healthy controls. Child maltreatment and neurocognitive performance were assessed in all participants. HPA negative feedback was analyzed using the dexamethasone suppression test after the administration of 0.25mg of dexamethasone. A total of 23 single-nucleotide polymorphisms were genotyped, and methylation levels at several CpGs in exons 1D, 1F and 1H of the GR gene were measured.

Results show that, beyond the influence of other covariables, NR3C1 single-nucleotide polymorphisms and methylation levels predicted performance in executive functioning and working memory tasks. No significant interactions or mediation relationships were detected.

Results suggest that genetic variations and epigenetic regulation of the GR gene are relevant factors influencing cognitive performance in MDD and could emerge as significant biomarkers and therapeutic targets in mood disorders and other stress-related disorders.