Reduced DNA Methylation of the Oxytocin Receptor Gene Is Associated With Anhedonia-Asociality in Women With Recent-Onset Schizophrenia and Ultra-high Risk for Psychosis

Abstract

Negative symptoms are recognized as a fundamental feature of schizophrenia throughout the disease course. Epigenetic alterations in the oxytocin receptor gene (OXTR) may be a key mechanism involved in social-emotional disturbances of schizophrenia. Here, we investigated OXTR methylation and its association with clinical and brain network connectivity phenotypes of negative symptoms, particularly anhedonia-asociality, in individuals with recent-onset schizophrenia (ROS) and at ultrahigh risk (UHR) for psychosis. Sixty-four ROS (39 women), 46 UHR (19 women), and 98 healthy individuals (52 women) participated in this study. OXTR methylation was quantified using the pyrosequencing method. A subset of participants (16 ROS, 23 UHR, and 33 healthy controls [HCs]) underwent a 5.5-minute resting-state functional magnetic resonance imaging to determine the relationship between OXTR methylation and the striatal-amygdala network functional connectivity (FC) underlying anhedonia-asociality. Both men and women with ROS and UHR showed significantly decreased OXTR methylation compared to HCs. In women with ROS and UHR, decreased OXTR methylation showed a significant correlation with increased anhedonia-asociality. FC of the striatal-amygdala network, positively associated with the severity of anhedonia-asociality, showed an inverse correlation with OXTR methylation. This study suggests that epigenetic alterations of OXTR, which can be detected before the development of full-blown psychosis, confer susceptibility to schizophrenia and play a crucial role in the manifestation of anhedonia-asociality, particularly in women.

Keywords: anhedonia-asociality; epigenetics; schizophrenia; ultrahigh risk for psychosis; oxytocin receptor gene.

Fig. 1.

Association between DNA methylation at CpG1 of OXTR1 and the severity of anhedonia-asociality in women with ROS and UHR (N = 58). OXTR, oxytocin receptor gene; ROS, recent-onset schizophrenia; UHR, ultrahigh risk for psychosis.

Fig. 2.

(A) Spatial map of the striatal network. (B) Spatial map of the amygdala network. (C) Between-group comparisons of the striatal-amygdala network FC. (D) Association between DNA methylation at CpG1 of OXTR1 and striatal-amygdala network FC. FC, functional connectivity; OXTR, oxytocin receptor gene; ROS, recent-onset schizophrenia; UHR, ultrahigh risk for psychosis; HCs, healthy controls; SEM, standard error of mean.