DRD4 methylation as a potential biomarker for physical aggression: An epigenome‐wide, cross‐tissue investigation

Epigenetic processes that regulate gene expression, such as DNA methylation (DNAm), have been linked to individual differences in physical aggression. Yet, it is currently unclear whether: (a) DNAm patterns in humans associate with physical aggression independently of other co‐occurring psychiatric and behavioral symptoms; (b) whether these patterns are observable across multiple tissues; and (c) whether they may function as a causal versus noncausal biomarker of physical aggression. Here, we used a multisample, cross‐tissue design to address these questions. First, we examined genome‐wide DNAm patterns (buccal swabs; Illumina 450k) associated with engagement in physical fights in a sample of high‐risk youth ( n  = 119; age = 16–24 years; 53% female). We identified one differentially methylated region in DRD4, which survived genome‐wide correction, associated with physical aggression above and beyond co‐occurring symptomatology (e.g., ADHD, substance use), and showed strong cross‐tissue concordance with both blood and brain. Second, we found that DNAm sites within this region were also differentially methylated in an independent sample of young adults, between individuals with a history of chronic‐high versus low physical aggression (peripheral T cells; ages 26–28). Finally, we ran a Mendelian randomization analysis using GWAS data from the EAGLE consortium to test for a causal association of DRD4 methylation with physical aggression. Only one genetic instrument was eligible for the analysis, and results provided no evidence for a causal association. Overall, our findings lend support for peripheral DRD4 methylation as a potential biomarker of physically aggressive behavior, with no evidence yet of a causal relationship.