Variation in DNA methylation of the oxytocin gene is associated with prosocial, reward-related, decision-making

Human and animal studies suggest a critical role for central oxytocin (OXT) in social behavior. While experimentally manipulating central OXT levels via intranasal administration is a well-suited noninvasive option in human research, existing findings are mixed, suggesting that the effects of exogenous OXT on social behavior are highly variable and dependent on other (e.g., biological) factors. Endogenous OXT synthesis is regulated by a wide range of molecular mechanisms including DNA methylation (DNAm). However, the link between DNAm of the OXT gene ( OXT ) and human social behavior has received little attention. We studied the relationship between OXT DNAm, intranasal OXT administration, and facets of human (pro-)social behavior and found preliminary evidence that OXT DNAm at three CpG sites (i.e., GRCh37/hg19=chr20: 3,052,319; chr20: 3,052,334; chr20:3,052,345) is negatively associated with trust game investments. Associations with (pro-)social traits or interactions between OXT DNAm and OXT administration on trusting behavior and generosity were not significant. Our results suggest that variation in OXT DNAm is associated with trusting behavior but no (main or moderating) effect of exogenous OXT administration was observed. Importantly, because functional indices of OXT gene expression or endogenous OXT levels were not incorporated into the present analyses, the findings cannot speak to whether DNAm variation translates into measurable differences in oxytocinergic system activity in the brain. Further, our findings highlight the need for future research examining whether, and how, OXT DNAm is related to reward-related processes and their neurobiological underpinnings, including potential interactions between oxytocinergic and other neuromodulatory systems implicated in reward processing (e.g., dopaminergic or serotonergic systems). Future studies should investigate the relationship between OXT DNAm and trust game investments, determine functional consequences on the molecular level, and directly assess whether, and how, OXT DNAm is related to neurobiological processes involved in prosocial, reward-related, behavior. • Variation in DNA methylation of the oxytocin gene is associated with trust game choices • No moderating effect of oxytocin manipulation on the observed associations • No significant associations with other prosocial traits • Potential interactions between oxytocinergic and other neuromodulatory systems • Future studies should assess functional molecular consequences