Bridging Genes and Behavior in Autism Spectrum Disorder: Contributions of OXTR Gene Variants and Methylation to Brain Connectivity Patterns

Abstract

Objective To investigate how genetic variants and epigenetic modification of the oxytocin receptor gene (OXTR) relate to resting-state functional connectivity (FC) alterations and core symptom severity in children with autism spectrum disorder (ASD). Methods We recruited 43 children with ASD and 54 typically developing (TD) children. Participants underwent OXTR genotyping and DNA methylation analysis (including CpG site 924), resting-state functional MRI, and standardized clinical assessments of ASD symptom severity. Group differences in within- and between-network FC were evaluated, and diagnosis-by-genotype/methylation interaction analyses were performed. Associations between FC measures and clinical severity scores were examined. Results Children with ASD showed decreased FC within and between major brain networks compared with TD children. OXTR genetic variants and hypermethylation further moderated these group differences. Specifically, risk alleles of two OXTR single nucleotide polymorphisms and hypermethylation at CpG 924 were associated with decreased FC in ASD but increased FC in TD children, suggesting a diagnosis-dependent, potentially compensatory pattern in typical development. FC measures were significantly associated with ASD severity scores. Conclusion These findings link OXTR genetic and epigenetic variation to network-level brain connectivity alterations and clinical symptoms in ASD, supporting an integrated neurobiological model that bridges molecular variation and behavior. Multimodal approaches incorporating epigenetics and neuroimaging may facilitate personalized, mechanism-based strategies for ASD.