Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity

Abstract

The role of oxytocin in social cognition has attracted tremendous interest in social neuroscience and psychiatry. Some studies have reported improvement in social symptoms following oxytocin treatment in autism spectrum disorders (ASD), while others point to endogenous factors influencing its efficiency and to mixed results in terms of long-term clinical benefits. Epigenetic modification to the oxytocin receptor gene (OXTR) in ASD could be an informative biomarker of treatment efficacy. Yet, little is known about the relationship between OXTR methylation, clinical severity, and brain function in ASD. Here, we investigated the relationship between OXTR methylation, ASD diagnosis (in N = 35 ASD and N = 64 neurotypical group), measures of social responsiveness, and resting-state functional connectivity (rsFC) between areas involved in social cognition and reward processing (in a subset of ASD, N = 30). Adults with ASD showed higher OXTR methylation levels in the intron 1 area compared with neurotypical subjects. This hypermethylation was related to clinical symptoms and to a hypoconnectivity between cortico-cortical areas involved in theory of mind. Methylation at a CpG site in the exon 1 area was positively related to social responsiveness deficits in ASD and to a hyperconnectivity between striatal and cortical brain areas. Taken together, these findings provide initial evidence for OXTR hypermethylation in the intron area as a potential biomarker for adults with ASD with less severe developmental communication deficits, but with impairments in theory of mind and self-awareness. Also, OXTR methylation in the exon 1 area could be a potential biomarker of sociability sensitive to life experiences.

Fig. 1. Differences in levels of methylation between neurotypical subjects (N = 64) and adults with autism spectrum disorders (ASD) (N = 35) in 21 fragments including 27 CpG sites of the MT2 region of the OXTR gene.

CpG 16 (b.p. −989) showed significant increase in methylation in ASD as compared with neurotypical subjects (t(97) = −4.38; α = 0.0024; P < 0.0001). The schematic representation of the MT2 region in the bottom of the figure indicates that the Exon 1 includes CpG 1 to CpG 13 and that Intron 1 includes CpG 14 to CpG 27. Errors bars are standard errors.

Fig. 2. Results of the general linear model that includes the social responsiveness scale (SRS-2) as the dependent variable and levels of methylation at CpG 5,6 (b.p. −1121, −1119) as well as age as predictors.

The X axis represents the predicted estimated value of both predictors in relation to the dependent variable. a Positive correlation between methylation at CpG 5,6 (b.p. −1121, −1119) and total scores of SRS-2 (χ² = 5.25, P < 0.05). b Negative correlation between methylation at CpG 16 (b.p. −989) and ADI-R total scores (χ² = 4.92; P < 0.05). c Correlations between methylation at CpG 16 (b.p. −989) and ADI-R subcomponents (χ² = 4.71; P < 0.05). SI social interaction, LC language and communication, RRB restricted and repetitive behavior. Dashed lines denote the 95% confidence interval.

Fig. 3. Brain resting-state functional connectivity (rsFC) between independent components (ICs) representing theory of mind (IC11 that includes the superior temporal sulcus) and self-awareness (IC20 that includes the posterior cingulate cortex) was negatively correlated with oxytocin receptor gene methylation levels.

a Negative correlation between FNC between IC1 and IC20 and methylation levels at CpG 16 (b.p. −989) (General linear model, ß = -0.404, χ² = 15.03, P < 0.0001). b Positive correlation between FNC between IC1 and IC20 and ADI-R total scores (r = 0.57, P < 0.003). The GICA-derived IC strength t-test maps have been thresholded at FDR q < 0.0001. Dashed lines denote the 95% confidence interval.

Fig. 4. Resting-state functional connectivity (rsFC) between independent components (ICs) representing reward processing correlates with oxytocin receptor methylation and social responsiveness scale (SRS-2) in ASD.

a Positive correlation between IC5 (that includes ventral striatum) and IC16 (that includes ventromedial prefrontal cortex) and methylation levels at CpG 5,6 (b.p. −1121, −1119) of the oxytocin receptor gene (ß = 0.062, χ² = 7.15, P < 0.009). b Negative correlation between IC5 (that includes ventral striatum) and IC18 (that includes anterior cingulate cortex and insula) and SRS-2 total scores (r = −0.41, P < 0.05). c Negative correlation between IC5 (that includes ventral striatum) and IC4 (that includes the amygdala) and SRS-2 total scores (r = −0.45, P < 0.05). The GICA-derived IC strength t-test maps have been thresholded at FDR q < 0.0001. Dashed lines denote the 95% confidence interval. vstriatum ventral striatum, vmPFC ventromedial prefrontal cortex, ACC anterior cingulate cortex, Amy amygdala.