Human DNA methylation and the cortisol response to an acute psychological stressor: A systematic review and...

The hypothalamic-pituitary-adrenal axis (HPA axis) is an important part of the stress response. The HPA axis may adapt to the environment in part through epigenetics, including DNA methylation. This pre-registered (OSF), PRISMA-compliant systematic review and meta-analysis aimed to evaluate the level of evidence for an association between DNA methylation and the cortisol response to an acute psychological stressor, a key marker of HPA axis function, in humans. PsycINFO, MEDLINE, Scopus, and Web of Science were searched on the 1st of September 2025 and risk of bias was evaluated using an original rubric. Thirty-nine studies were included, with mixed results. Meta-analyses revealed support for an association between NR3C1 methylation and a stronger cortisol response in infants (r = 0.26, p = .01), but not other age groups (r = -0.01, p = . 85). There was some tentative evidence for an association between SLC6A4 methylation and a weaker cortisol response (r = -0.15, p = .056), but the effect was not significant. There was preliminary (non-meta-analytic) support for LEP, NR3C2, OXTR, and SKA2. The evidence to date must be considered low certainty, due to a combination of small sample sizes, incomplete reporting, substantial methodological and conceptual heterogeneity, a high likelihood of residual confounding, and a reliance on outdated and unreliable candidate gene methods. Given the low certainty of the evidence, it is not yet possible to draw any strong conclusions. Directions for research include a collaborative, protocolised, methylome-wide meta-analysis and a focus on genomic loci that may be more strongly correlated between brain and peripheral tissue. This review received no specific funding.