Genome-wide DNA methylation profiles in the raphe nuclei of patients with autism spectrum disorder

Abstract Background: Autism spectrum disorder (ASD) has a strong genetic basis, yet its genetic complexities remain elusive. Current research highlights environmental factors and epigenetic processes, such as DNA methylation, as crucial in ASD development. This study explored epigenetic modifications using postmortem brain samples from ASD subjects and controls.Methods: We comprehensively analyzed genome-wide DNA methylation profiles in the dorsal raphe brain region using the Infinium HumanMethylation450 BeadChip (Illumina). In addition, quantitative PCR was used to investigate mRNA expression levels of genes that demonstrated differential methylation in ASD.Results: We identified differentially methylated regions (DMRs) and individual-specific DMRs (IS-DMRs) between ASD and control subjects. These DMRs and IS-DMRs were located across various genomic regions, including promoters, gene bodies, 3ʹ UTRs, and intergenic regions. Notably, we found hypermethylation in genes related to olfaction (e.g., OR2C3), which is regulated by serotonin. Hypomethylated genes in IS-DMRs were linked to ASD and developmental disorders. Additionally, we observed that the hypomethylation of promoter-associated CpG islands in RABGGTB, a gene related to autophagy and synaptic function, corresponded with its increased expression.Conclusions: Our findings reveal extensive DNA methylation changes in critical genomic regions, shedding light on potential mechanisms underlying ASD. The identification of RABGGTB as a novel candidate gene, not listed in the SFARI database, underscores its significance and warrants further research to explore its role in ASD diagnosis. This study enhances our understanding of the epigenetic landscape in ASD, emphasizing the interplay between genetic and environmental factors in its pathophysiology.