Epigenome-wide DNA methylation in externalizing behaviours: A review and combined analysis

DNA methylation (DNAm) is one of the most frequently studied epigenetic mechanisms facilitating the interplay of genomic and environmental factors, which can contribute to externalizing behaviours and related psychiatric disorders. Previous epigenome-wide association studies (EWAS) for externalizing behaviours have been limited in sample size, and, therefore, candidate genes and biomarkers with robust evidence are still lacking. We 1) performed a systematic literature review of EWAS of attention-deficit/hyperactivity disorder (ADHD)- and aggression-related behaviours conducted in peripheral tissue and cord blood and 2) combined the most strongly associated DNAm sites observed in individual studies (p < 10-3) to identify candidate genes and biological systems for ADHD and aggressive behaviours. We observed enrichment for neuronal processes and neuronal cell marker genes for ADHD. Astrocyte and granulocytes cell markers among genes annotated to DNAm sites were relevant for both ADHD and aggression-related behaviours. Only 1 % of the most significant epigenetic findings for ADHD/ADHD symptoms were likely to be directly explained by genetic factors involved in ADHD. Finally, we discuss how the field would greatly benefit from larger sample sizes and harmonization of assessment instruments.

Automated summary

DNA methylation is an important epigenetic mechanism that plays a role in the interaction between genes and the environment, and is associated with externalizing behaviors and psychiatric disorders. Previous studies on externalizing behaviors have been limited in sample size, leading to a lack of candidate genes and biomarkers with strong evidence. In this study, we conducted a systematic literature review and identified candidate genes and biological systems for attention-deficit/hyperactivity disorder (ADHD) and aggressive behaviors based on epigenome-wide association studies (EWAS) conducted in peripheral tissue and cord blood. The findings suggest the involvement of neuronal processes and cell marker genes in ADHD, and the relevance of astrocytes and granulocytes to both ADHD and aggression-related behaviors. Only a small proportion of the significant epigenetic findings can be directly explained by genetic factors associated with ADHD. Larger sample sizes and harmonization of assessment instruments are needed to advance the field.