Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain

In humans, the neuropeptide oxytocin plays a critical role in social and emotional behavior. The actions of this molecule are dependent on a protein that acts as its receptor, which is encoded by the oxytocin receptor gene (OXTR). DNA methylation of OXTR, an epigenetic modification, directly influences gene transcription and is variable in humans. However, the impact of this variability on specific social behaviors is unknown. We hypothesized that variability in OXTR methylation impacts social perceptual processes often linked with oxytocin, such as perception of facial emotions. Using an imaging epigenetic approach, we established a relationship between OXTR methylation and neural activity in response to emotional face processing. Specifically, high levels of OXTR methylation were associated with greater amounts of activity in regions associated with face and emotion processing including amygdala, fusiform, and insula. Importantly, we found that these higher levels of OXTR methylation were also associated with decreased functional coupling of amygdala with regions involved in affect appraisal and emotion regulation. These data indicate that the human endogenous oxytocin system is involved in attenuation of the fear response, corroborating research implicating intranasal oxytocin in the same processes. Our findings highlight the importance of including epigenetic mechanisms in the description of the endogenous oxytocin system and further support a central role for oxytocin in social cognition. This approach linking epigenetic variability with neural endophenotypes may broadly explain individual differences in phenotype including susceptibility or resilience to disease.