DNA methylation of OXTR is associated with parasympathetic nervous system activity and amygdala morphology

Abstract

Oxytocin has anxiolytic properties whose mechanisms of action are still being identified. DNA methylation in the promoter region of the oxytocin receptor gene (OXTR), an epigenetic modification that putatively reflects a downtuning of the oxytocin system, has previously been implicated in the regulation of fear-related responses through the amygdala. In this study, we attempted to characterize the relationship between methylation of OXTR and anxiogenesis using two distinct endophenotypes: autonomic nervous system activity and subcortical brain structure. In 79 participants, we found that increased OXTR methylation is associated with attenuated resting parasympathetic tone, measured using high-frequency heart rate variability. Further, we found that this relationship is mediated by brain morphology, such that OXTR methylation is associated with increased gray matter of the central amygdala which is, in turn, associated with decreased parasympathetic tone. These results further our understanding of epigenetic regulation of the human oxytocin system and its role in anxiogenesis.

Fig. 1

Higher OXTR methylation is associated with lower baseline HF-HRV. Greater methylation levels of OXTR are associated with low resting HF-HRV, measured in milliseconds squared (ms²).

Fig. 2

Gray matter density is associated with OXTR methylation and baseline HF-HRV. (A)OXTR methylation positively is associated with gray matter in the right central amygdala, peak voxel xyz = 22, −10, −8, cluster extent = 7 voxels, P = 0.032; cluster displayed on coronal slice at z = −8. (B) Higher percent methylation is associated with increased gray matter volume, AU, arbitrary units.(C) Gray matter volume is in turn associated with lower baseline log HF-HRV, ms², milliseconds squared.

Fig. 3

Central amygdala gray matter density mediates the relationship between OXTR methylation and HF-HRV. Figure 3 illustrates the mediational relationship between OXTR methylation, parasympathetic nervous system activity (log HF-HRV) and central amygdala gray matter. Path c reflects the total effect of the predictor on the dependent variable, while path c’ reflects the direct effect and paths ab reflect the indirect effect of the mediator, ns = not significant, ^* corresponds to a P value smaller than the significance level of 0.05.