Background: Epigenetic signatures have emerged as central mechanisms explaining how life stress may confer long-term changes in stress response systems and disease susceptibility. In a series of studies we aimed to elucidate how DNA methylation profiles in the serotonin transporter gene (SLC6A4) relate to system-wide changes in stress sensitivity.

Methods: Quantitative methylation at 83 CpG sites within a promoter-associated CpG island of SLC6A4 was analyzed by bisulfite pyrosequencing from blood-derived DNA samples. We further applied a resting state functional magnetic resonance imaging approach to identify changes in stress-related brain networks associated with SLC6A4 methylation in healthy adults. Moreover, participants were exposed to a laboratory stressor (Trier Social Stress Test) to investigate cortisol stress reactivity as a function of SLC6A4 methylation.

Results: Collectively, our findings suggest that epigenetic signatures in SLC6A4 are predictive of clinically relevant changes in stress sensitivity markers. Specifically, we observed a positive association of SLC6A4 methylation and resting state amygdala functional connectivity with brain areas of the salience network (N = 74). This pattern is known to facilitate the detection and processing of negative stimuli and reflects a common feature of affective disorders. Moreover, SLC6A4 methylation levels were found to moderate the effect of genetic variation in the serotonin transporter gene (5-HTTPR) on cortisol stress reactivity (N = 184).

Conclusions: Concluding from our studies, investigating combined effects of genetic and epigenetic variation might allow the detection of more robust effects in future genetic association studies and further advance our understanding regarding the genetic basis of stress susceptibility and disease risk.