DNA Methylation of the Oxytocin Receptor (OXTR) and Associated Genes in Autism Spectrum Disorder (ASD)

Background: Autism spectrum disorders (ASD) are a group of childhood onset neurodevelopmental disorders characterized by problems in social interaction and communication as well as repetitive behaviours. Studies in children with autism have demonstrated lower levels of oxytocin (OXT) in the blood compared to typically developing, age-matched children. It has been suggested that dysfunction of the OXT pathway is associated with features of autism such as repetitive behaviour and impaired social cognition. Treatment of ASD patients with OXT to ameliorate these behaviours has been proposed.

Objectives: Previously a study in a small population reported increased DNA methylation of the oxytocin receptor (OXTR) in lymphocytes of patients with autism. These changes were also demonstrated in post-mortem samples from the temporal cortex of autism patients. Our objective was to determine the DNA methylation pattern of the OXTR promoter and investigate the methylation of genes in both the oxytocin (OXT) and vasopressin (AVP) pathways in a larger cohort of patients with ASD.

Methods: Blood DNA from patients with ASD were sodium bisulfite converted. DNA methylation patterns of genes in the OXT and the AVP pathways were assessed using the Illumina Human Methylation27K microarrays or targeted pyrosequencing. Data was extracted from the microarray data for AVP, OXT, AVPR1A, AVPR1B, AVPR2 and the promoter of OXTR. Methylation of the 5’UTR of OXTR, a region previously described to have altered DNA methylation in ASD and not represented on the microarray, was assessed using quantitative sodium bisulfite pyrosequencing of 8 CpG in a cohort of ASD patients and controls. 

Results: Targeted DNA methylation analysis of the 5’-UTR CpG island of OXTR demonstrated no difference in DNA methylation of the region between ASD cases and controls.  However, in 8% of the male ASD samples there was an increase in DNA methylation at one of the CpG sites previously reported to have increased methylation in association with ASD. There was no statistical DNA methylation difference in AVP, OXT, AVPR1A, AVPR1B, AVPR2 or the promoter of OXTR between cases and controls.

Conclusions: DNA methylation alterations in the OXT pathway may be relevant to both ASD phenotype and treatment options.  Methylation of OXTR could be an important modulator of response to oxytocin (OXT) treatment in which case the methylation pattern of OXTR could be a useful tool in determining the appropriateness of OXT treatment for individual patients.