DNA Methylation of the Oxytocin Receptor Gene As a Predictor of Social Brain Function in Families with ASD

Background:  

Oxytocin (OXT) is a sexually dimorphic hormone associated with important social perceptual and affiliative processes^1–6—processes known to to be impacted in ASD. Moreover, OXT levels may be depressed in ASD⁷, and recent work demonstrates that OXT administration to persons with ASD is associated with a more “neurotypical” brain response to social stimuli.

OXT’s action is mediated in humans via the oxytocin receptor (OXTR)⁸. Several genetic variants of OXTR have been associated with autism spectrum disorders^9–12. However, the function of OXTR is likely to be affected not just by genetic variation but also by epigenetic factors—that is, modifications to chromatin that regulate gene expression. Important preliminary research suggests that DNA methylation (a form of epigenetic modification most commonly associated with transcriptional silencing) of OXTR could play a role in social functioning and ASD status. Specifically, degree of OXTR methylation has been associated with variability in social brain function in health adults¹³ and increased OXTR methylation is associated with presence of ASD¹⁴.

This evidence suggests that an investigation of OXTR methylation and its relation to ASD symptoms and social brain function may be informative about ASD etiology. Additionally, the sexually dimorphic action of OXT makes it worthwhile to examine whether and how these relationships vary by gender.

Objectives:  

• Characterize relationships among OXTR methylation, social behavior, and social brain function for individuals with ASD and their families
• Investigate whether and how these relationship vary as a function of gender

Methods:  

 We leverage the unique characteristics of an ACE network focused on the multimodal assessment of girls with ASD to recruit deeply-phenotyped girls and boys with ASD and their families. All family members provide samples of whole blood from which mononuclear cell DNA is isolated for OXTR methylation analysis. Children with ASD and their unaffected siblings additionally participate in fMRI paradigms focused on processes of both lower- (point-light displays of biological motion) and higher-order (Heider & Simmel¹⁵ animations) social perception.  Percent OXTR methylation is included as the regressor of interest in analyses of fMRI data to determine regions in which methylation is related to social brain response.

Results:  

To date we have collected usable blood and fMRI data from 4 affected families (parents, probands, and unaffected siblings) as well as 5 control families. We hypothesize that 1) individuals with ASD will display a higher level of OXTR methylation, on average, than either their unaffected relatives or typically developing controls; 2) unaffected siblings will display a positive relationship between social brain activity and OXTR methylation, indicating a compensatory response; 3) individuals with ASD will display a negative or attentuated relationship between social brain activity and OXTR methylation; and 4) these relationships will be stronger for males than females.

Conclusions:

This is the first study to examine the relationship between OXTR methylation and social brain function among individuals with ASD. Understanding the contribution of epigenetic factors to neuroendophenotypes of ASD and gender differences in the disorder will advance our understanding of the etiology of ASD more broadly.