Epigenomic mediation after adverse childhood experiences: a systematic review and meta-analysis

Epigenetic mechanisms are potential mediators of the physiological response to abuse by altering the genetic predisposition of the cellular response to the environment, leading to changes in the regulation of multiple organ systems. This study was established to review the epigenetic mechanisms associated with childhood abuse as well as the long-term determinants that these epigenetic changes may have on future illness. We retrospectively analysed the effect of exposure to adverse childhood experiences (ACEs, specifically those relating to childhood maltreatment) between the ages of 0 and 16 years on the human epigenome, as well as possible clinical associations. After meeting inclusion and exclusion criteria, 36 articles were included in this systematic review. Eight of these studies did not find a relationship between childhood maltreatment and DNA methylation. Of the remaining 28 studies, nine were genome-wide association studies, whereas the rest were candidate gene studies, mainly studying effects on neuroendocrine, serotoninergic and immunoregulatory systems. Meta-analysis of correlation coefficients from candidate gene studies estimated an association of childhood adversity and DNA methylation variation at r = 0.291 (P < 0.0001), and meta-analysis of two epigenome-wide association studies (EWASs) identified 44 differentially methylated CpG sites. In conclusion, childhood maltreatment may mediate epigenetic mechanisms through DNA methylation, thereby affecting physiological responses and conferring a predisposition to an increased risk for psychopathology and forensic repercussions. Similar evidence for somatic illnesses is not yet available. KEY POINTS: Adverse childhood experiences are associated with increased mortality partly explained by acquired epigenetic changes. There is a positive correlation between childhood abuse and DNA methylation at specific gene sites. The cumulative effect of different types of childhood abuse and neglect may lead to changes in DNA methylation. Epigenome changes associated with childhood abuse appear to be involved in the development of psychiatric illness in adulthood. Studying epigenetic changes may have important public health and forensic applications in the future.