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

Epigenetic signatures, such as DNA methylation (DNA_M), 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 DNA_M 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 DNA_M in 183 adults. Whole blood samples were drawn for DNA_M 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 DNA_M 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 DNA_M 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 DNA_M. By contrast, no such effect occurred under conditions of high SLC6A4 DNA_M, 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.