Serotonin transporter gene methylation predicts long-term cortisol concentrations in hair.

Epigenetic signatures, such as DNA methylation (DNAM), have been implicated in long-term dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis and related health risks. Based on a wealth of neuroendocrine studies on genetic polymorphisms in the serotonin transporter gene (SLC6A4), this locus constitutes a key candidate to explore associations of DNAM patterns and HPA-axis functioning. The few studies addressing this link so far exclusively relied on spot measurements of HPA-axis activity, which may not adequately reflect cortisol output over prolonged periods of time. To address this gap, hair cortisol concentrations (HCC), a valid measure of integrated long-term cortisol levels, were utilized to investigate endocrine correlates of SLC6A4 DNAM in 183 adults. Whole blood samples were drawn for DNAM analyses of 83 CpG sites within a 799-bp promoter-associated CpG island of SLC6A4 via bisulfite pyrosequencing. In addition, all participants were genotyped for the serotonin transporter polymorphism (5-HTTLPR). First, results revealed a significant negative association of SLC6A4 DNAM and HCC. Second, there was no significant main effect of 5-HTTLPR genotype on HCC when analyses were conducted on the basis of both bi-allelic classification and the 5-HTTLPR/rs25531 mini-haplotype. Third, the current data revealed a significant interaction of SLC6A4 DNAM and 5-HTTLPR genotype on HCC. Comparable to the pattern we had previously observed concerning cortisol stress reactivity, the S allele relates to increased HCC in individuals displaying low levels of SLC6A4 DNAM. By contrast, no such effect occurred under conditions of high SLC6A4 DNAM, indicating that epigenetic changes may compensate for genotype-dependent differences in long-term cortisol output. Together, respective findings support the idea of an epigenetic contribution to long-term HPA-axis activity and further highlight the usefulness of combining genetic and epigenetic information in future neuroendocrine studies.