Evaluating the challenges and reproducibility of studies investigating DNA methylation signatures of psychological stress.

Psychological stress can increase the risk of a wide range of negative health outcomes. Studies have been completed to determine if DNA methylation changes occur in the human brain because of stress and are associated with long-term effects and disease, but results have been inconsistent. Human candidate gene studies (150) and epigenome-wide association studies (67) were systematically evaluated to assess how DNA methylation is impacted by stress during the prenatal period, early childhood and adulthood. The association between DNA methylation of NR3C1 exon 1F and child maltreatment and early life adversity was well demonstrated, but other genes did not exhibit a clear association. The reproducibility of individual CpG sites in epigenome-wide association studies was also poor. However, biological pathways, including stress response, brain development and immunity, have been consistently identified across different stressors throughout the life span. Future studies would benefit from the increased sample size, longitudinal design, standardized methodology, optimal quality control, and improved statistical procedures.