Genetic and epigenetic signatures associated with plasma oxytocin levels in children and adolescents with autism spectrum disorder

Abstract

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome‐wide profiles of DNA‐methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA‐methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT‐based interventions. Lay Summary Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non‐DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT‐based treatment.

A targeted long-read sequencing approach questions the association of OXTR methylation with high-functioning autism

“…However, the relevance of CpGs -901, -924 and -934 for OXTR expression postulated in preliminary studies is questioned in a recent study. Siecinski et al analyzed three CpG sites within the MT2 region of OXTR previously associated with ASD and OXTR expression (-901, -924, -934) by targeted pyrosequencing, but found no significant association with plasma oxytocin levels [ 19 ].…”

At the head and heart of oxytocin’s stress-regulatory neural and cardiac effects: a chronic administration RCT in children with autism

“…Finally, there is a growing awareness that oxytocin nasal spray administration effects may not be uniform and that distinct context-and/or person-dependent factors may hamper or facilitate treatment responses 35 . Since oxytocin's effects on brain function and behavior are known to be mediated by the prevalence of oxytocin receptors as determined by the oxytocin receptor gene (OXTR), it is increasingly put forward that (epigenetic) variations of OXTR may form an important factor for explaining variable treatment responses [36][37][38] , but empirical evidence is largely lacking. To investigate the impact of OXTR epigenetics, we examined whether variability in neural effects is mediated by variability in baseline (pre-nasal spray) DNA methylation of the OXTR gene.…”

At the Head and Heart of Oxytocin’s Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism

“…Finally, there is a growing awareness that oxytocin nasal spray administration effects may not be uniform but that distinct context-and/or person-dependent factors may hamper or facilitate treatment responses [35]. Since oxytocin's effects on brain function and behavior are mediated by the prevalence of oxytocin receptors as determined by the oxytocin receptor gene (OXTR), it is increasingly put forward that (epigenetic) variations of OXTR may form an important factor for explaining variable treatment responses [36][37][38]. However, empirical evidence in this area is largely lacking.…”