DNA Methylation of the Oxytocin Receptor Gene Predicts Variability in Brain Response to Social Stimuli Among Children with Autism Spectrum Disorder

Thursday, May 12, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
A. Jack1, T. S. Lillard2, D. R. Oosting1,3, J. P. Morris2, K. Pelphrey1 and J. J. Connelly2, (1)Yale Child Study Center, Yale School of Medicine, New Haven, CT, (2)Department of Psychology, University of Virginia, Charlottesville, VA, (3)Psychology, University of Massachusetts, Boston, MA
Background: The hormone oxytocin influences social perception, and variants of the oxytocin receptor gene (OXTR) have been associated with autism spectrum disorder (ASD)1. However, epigenetic modifications that impact gene transcription also impact phenotypic variability. One such modification is DNA methylation, which allows for transcriptional silencing as well as temporal control of gene expression. Previously, we (JJC) found elevated OXTR DNA methylation (OXTRm) in individuals with ASD2 accompanied by decreased oxytocin receptor transcription in superior temporal sulcus (STS), a site associated with social perception. Subsequently, we (AJ, JPM, JJC) demonstrated that blood-derived OXTRm in healthy adults predicts variability in response to social stimuli in key brain sites, including STS3,4. These findings suggest that OXTRm is atypical in ASD, and variability in OXTRm within the typical range predicts social brain function. However, the relationship between OXTRm and functional brain outcomes within ASD is yet unexplored. Here we describe associations between OXTRm and brain response to human motion, among children with and without ASD.

Objectives: To characterize 1) how OXTRm interacts with ASD diagnosis to predict brain response to human motion, and 2) how sex differences in OXTRm interact with diagnostic status to predict brain response to human motion. 

Methods: We enrolled 11 children with ASD (5 girls) and 14 typically developing (TD) children (6 girls). Blood was collected in mononuclear cell separating tubes and samples spun to separate the mononuclear cell fraction as per product protocol, and DNA was isolated. OXTRm was assessed at CpG sites ‑860, ‑924, and ‑934. Epigenotyping procedures are described in3,4. Scans included a T1-weighted anatomical image and a BOLD fMRI scan. The Biological Motion paradigm features interleaved blocks of coherent (BIO) and scrambled (SCRAM) point-light displays of human movement and recruits brain regions involved in social perception, including STS5. We assessed where BIO > SCRAM brain activity varied as a function of OXTRm, and where this relationship differed by diagnosis and sex (z = 2.3, p = 0.05, whole-brain cluster-corrected).  

Results: Children with ASD with higher methylation at sites ‑934 and ‑924 had weaker response to human motion in social brain regions including bilateral STS, while TD children with higher methylation showed stronger response in these regions (Fig1). This finding suggests compensatory social brain activity in children with higher epigenetic risk but no expression of the disorder, and a lack of such compensation in ASD. Additionally, at sites ‑860, ‑924, and ‑934, higher methylation was associated with a weaker response in occipitotemporal regions including STS and fusiform gyrus, but only in girls with ASD. 

Conclusions: These results suggest that variability in OXTRm holds promise for helping to explain processes of ASD risk and protection, including those that may differ by sex.

1.   Yrigollen et al. Biol. Psychiatry 63:911–6 (2008).

2.   Gregory et al. BMC Med. 7:62 (2009).

3.   Jack, Connelly, & Morris. Front. Hum. Neurosci. 6:280 (2012).

4.   Puglia, Lillard, Morris, & Connelly. Proc. Natl. Acad. Sci. 112:3308–3313 (2015).

5.   Kaiser, M. D. et al. Proc. Natl. Acad. Sci. 107:21223–8 (2010).