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

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 SummaryOxytocin (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.

Automated summary

This study investigated the impact of genetic and epigenetic variations on oxytocin levels in the blood. By analyzing the integration of genome profiles, transcriptional activity, and genetic variation with blood oxytocin levels in 290 participants with autism enrolled in an oxytocin clinical trial, genetic variants associated with blood oxytocin levels were identified, some of which were located in known autism risk genes. The study also showed a statistically significant association between blood oxytocin levels and gene expression and epigenetic profiles across multiple gene pathways. These findings broaden our understanding of the influence of the peripheral oxytocin system and its interaction with the complex etiology of autism and oxytocin-based treatments in future studies.