Associations of SLC6A4 methylation with salivary cortisol, salivary alpha-amylase, and subjective stress in everyday life

Dysregulations of the hypothalamic-pituitary-adrenal (HPA) and sympatho-adrenal medullary (SAM) axis are associated with mental and somatic illness. However, there is lack of knowledge regarding the molecular mechanisms underlying these effects. Epigenetic states in the serotonin transporter gene (SLC6A4) were shown to be associated with stress in various forms. We hypothesized that levels of DNA methylation (DNAm) of SLC6A4 would be associated with altered SAM- and HPA regulation in daily life. N = 74 healthy persons participated in the study. An ecological momentary assessment (EMA) approach was used to assess indicators of stress in daily life. Each day included six concurrent assessments of saliva, to quantify cortisol (sCort; HPA axis) and alphaamylase (sAA; SAM axis), and to assess self-reports on subjective stress. To assess SLC6A4 DNAm, peripheral blood was drawn and analyzed via bisulfite pyrosequencing. All data were assessed in two waves three months apart, each including two days of EMA and the assessment of SLC6A4 DNAm. Data were analyzed using multilevel models. On the between-person level, higher average levels of SLC6A4 DNAm were associated with higher average levels of sAA, but not with average levels of sCort. On the within-person level, higher levels of SLC6A4 DNAm were associated with lower levels of sAA and sCort. There were no associations of subjective stress with SLC6A4 DNAm. The results help to clarify the association between environmental stress and stress axes regulation, pointing towards an important role of differential within- and between-person effects of SLC6A4 DNAm, which might shape this association.

Automated summary

This study found that levels of DNA methylation (DNAm) of the serotonin transporter gene (SLC6A4) were associated with dysregulation of the sympatho-adrenal medullary (SAM) and hypothalamic-pituitary-adrenal (HPA) axis. In healthy individuals, higher levels of SLC6A4 DNAm were associated with higher levels of alpha-amylase (sAA), but not with cortisol (sCort) levels. Furthermore, within-person analysis showed that higher levels of SLC6A4 DNAm were associated with lower levels of both sAA and sCort. These results provide insight into the role of SLC6A4 DNAm in the association between environmental stress and stress axes regulation.