Objectives: To identify epigenetic alterations in autism spectrum disorders (ASD), we examined 41 post-mortem brain samples from cases and controls, focused on 3 brain regions, as well as blood samples from 8 ASD-discordant monozygotic twins.
Methods: We developed new tools for genome-scale epigenetic analysis, including array-based and whole genome bisulfite sequencing, and applied these to the study of ASD. These include robust statistical approaches to the Illumina 450K DNA methylation array such as "bump hunting," and novel approaches to whole genome bisulfite sequencing (WGBS). These will likely be of significant value to others in the field.
Results: 65 autism-related differentially methylated regions (DMRs) were identified, with statistical significance (genome-wide FWER < 0.01 or replication nominal P < 0.05) and magnitude of methylation change greater than 5%. Replicating, statistically significant differences involved genes and/or pathways related to genes with mutational mechanisms reported at much lower frequency.
Conclusions: The DMRs identified in the first phase of this research represent the first set of genomic regions commonly altered in ASD, and the biological targets identified are plausible autism candidates. The frequency of alteration is much higher than that of mutational variation, suggesting that epigenetic changes may explain a much higher fraction of ASD than conventional mutation acting alone. The results of this study open the door to novel diagnostic and therapeutic approaches to common autism.