Human DNA methylation and the cortisol response to an acute psychological stressor: a systematic review and meta-analysis

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 = .26, p = .01), but not other age groups (r = -.01, p = . 85). There was some tentative evidence for an association between SLC6A4 methylation and a weaker cortisol response (r = -.15, p = .056), but the effect was not significant. There was preliminary (non-meta-analytic) support for LEP, NR3C2, OXTR, and SKA2. The mixed results may be a product of confounding, small sample sizes, and candidate gene methods. They may also reflect a true but complex relationship, observable only in certain populations (e.g., infants) or in conjunction with other biological or environmental factors (e.g., antidepressants). We propose several directions for research, including a collaborative, pre-registered 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.