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. 2015 Mar 17;112(11):3308-13.
doi: 10.1073/pnas.1422096112. Epub 2015 Feb 9.

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

Meghan H Puglia  1 , Travis S Lillard  1 , James P Morris  2 , Jessica J Connelly  2
Affiliations

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

Meghan H Puglia et al. Proc Natl Acad Sci U S A. .

Abstract

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.

Keywords: OXTR; epigenetics; fMRI; oxytocin receptor; social perception.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Individuals with increased methylation of OXTR display elevated amygdala response to angry and fearful faces. Mean Z statistic values are plotted against percent OXTR methylation for each participant (n = 98). Gray shading indicates 95% confidence interval around the best-fit line. (Inset) Z statistic map of voxels shows significant main effect of OXTR methylation depicted in MNI space (y = 0), FDR corrected at q < 0.05. ROI is depicted in blue.
Fig. 2.
Fig. 2.
Methylation of OXTR predicts activity in brain regions previously associated with emotion and face perception. Z statistic map of voxels shows a significant positive main effect of OXTR methylation on BOLD activity for faces > ovals contrast within ROI, FDR corrected at q < 0.05. Images are depicted in MNI space (Top, x = 2, y = 3, z = –2; Bottom, x = 38, y = –59, z = –18). ACC, anterior cingulate cortex; Amyg, amygdala; FG, fusiform gyrus; Ins, insular cortex; LOC, lateral occipital cortex; NAcc, nucleus accumbens; pSTS, posterior superior temporal sulcus.
Fig. 3.
Fig. 3.
OXTR methylation predicts amygdala connectivity within brain regions important for emotion regulation and face perception. Z statistic map of voxels shows a significant negative main effect of OXTR methylation on right amygdala functional connectivity for faces > ovals contrast within ROI, FDR corrected at q < 0.05. Images are depicted in MNI space (Top, x = –3, y = 14, z = –7; Middle, x = –20, y = 22, z = 2; Bottom, x = –36, y = –74, z = –16). (Inset) Right amygdala seed region (y = –4). ACC, anterior cingulate cortex; C/Pu, caudate/putamen; FG, fusiform gyrus; IFG, inferior frontal gyrus; Ins, insular cortex; LOC, lateral occipital cortex; OFC, orbitofrontal cortex; pAC, paracingulate gyrus; Thal, thalamus.
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