ABSTRACT
Autism spectrum disorders (ASD) are characterized by impairments in social communication and increased repetitive behaviors. ASD etiology is complex, involving multiple genetic and environmental risks. Epigenetic modifications are poised at the interface between genes and environment and are predicted to reveal insight into the gene networks, cell types, and developmental timing of ASD etiology. Here, whole-genome bisulfite sequencing (WGBS) was used to examine DNA methylation in ASD and control frontal cortex samples. Systems biology approaches were leveraged to integrate methylation differences with relevant genomic datasets, revealing ASD-specific differentially methylated regions (DMRs) are significantly enriched for known neuronal and microglial regulatory elements, including cell-type-specific enhancers and transcription factor binding sites. ASD DMRs were also significantly enriched for known ASD genetic risk factors, including both common inherited and rare de novo variants. Weighted gene co-expression network analysis (WGCNA) revealed enrichment of ASD DMRs within developmental expression modules of brain and isolated microglia. Microglial modules identified dysregulated genes in maternal immune activation models of ASD. Weighted gene body co-methylation network analysis revealed a module characterized by hypomethylation of clustered protocadherin genes. Together, these results demonstrate an epigenomic signature of ASD in frontal cortex shared with known genetic and immune etiological risk. Epigenomic insights into cell types and gene pathways will aid in defining therapeutic targets and early biomarkers at the interface of genetic and environmental ASD risk factors.
