Genome-Wide DNA Methylation Profiling of Peripheral Blood Mononuclear Cells Reveals Epigenetic Signatures in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder caused by the interaction between genetic and environmental influences, potentially mediated by epigenetic mechanisms such as DNA methylation. Genome-wide DNA methylation profiling was performed using the Infinium MethylationEPIC v2.0 array on peripheral blood mononuclear cells (PBMCs) from 100 children with ASD and 50 typically developing controls. Differential methylation analyses were conducted by adjusting for age, sex, and estimated blood-cell-type composition as covariates. Functional enrichment, SFARI gene-overlap analysis, and cross-cohort validation were performed. We identified 3507 differentially methylated positions (DMPs) in the ASD cohort. Functional enrichment revealed pathways involved in neuronal signaling, synaptic activity, and immune regulation, suggesting coordinated neurodevelopmental and immune processes in ASD. Stratification by clinical severity demonstrated common and unique biological characteristics between the moderate and severe ASD groups. Furthermore, DMP-associated genes significantly overlapped with high-confidence ASD risk genes from the SFARI database and established transcriptomic signatures of neurodevelopmental disorders. Comparisons with independent post mortem brain tissue and peripheral blood datasets revealed partial overlap and directional concordance. However, the strength of concordance varied across datasets and was limited in the most directly comparable peripheral blood cohort. Our findings suggested that DNA methylation profiling of PBMCs provided peripheral epigenetic signatures and candidate loci for further validation in larger independent cohorts.