Increased methylation of NR3C1 and SLC6A4 is associated with blunted cortisol reactivity to stress in major depression

Background: Epigenetic changes are considered the main mechanisms behind the interplay of environment and genetic susceptibility in major depressive disorder (MDD). However, studies focusing on epigenetic dysregulation of the HPA axis stress response in MDD are lacking. Our objective was to simultaneously asses DNA methylation of the glucocorticoid receptor gene (NR3C1) and serotonin transporter gene (SLC6A4) and HPA axis response to stress in MDD. Methods: We recruited 80 depressed inpatients and 58 gender and age matched healthy controls. All participants underwent the Trier Social Stress Test (TSST) and salivary cortisol was repeatedly measured to assess HPA axis reactivity. DNA methylation of the NR3C1 (exon 1 F) and SLC6A4 CpG islands was quantified from whole blood DNA. In the MDD group, clinical assessment was repeated at 8-week follow-up to test the predictive potential of DNA methylation for symptom improvement. Results: Depressed patients had blunted cortisol reactivity to TSST compared to healthy controls (p = 0.01). In addition, they presented with increased average SLC6A4 (p = 0.003) and NR3C1 methylation (p = 0.03), as well as methylation of two individual NR3C1 CpG loci overlapping with the NGFI-A-binding sites (CpG12 and CpG20). Methylation of one of these two loci (CpG20) predicted lower symptom improvement at the follow-up (p = 0.007). Both, average NR3C1 and SLC6A4 methylation were associated with lower cortisol reactivity in the MDD group and explained about 16% of variability in cortisol response to TSST. Conclusions: We provide evidence of the role of NR3C1 and SLC6A4 DNA methylation in HPA axis dysregulation in MDD, which needs to be further explored.