Abstract
DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.
Highlights
Progress in understanding the genetic basis of autism spectrum disorder (ASD) has been substantial in recent years, with the development of microarray technologies allowing the identification of copy number variants associated with the disorder [1] and massively-parallel sequencing focused on protein-coding exons allowing insights into smaller mutational events disrupting gene function [2,3]
The studies were performed on individuals with ASD and typically developing controls, all born to mothers at least 35 years of age at the time of birth
We found the cells from individuals with ASD to have changes in DNA methylation at a number of loci, especially near genes encoding proteins known to interact with those already implicated in ASD
Summary
Progress in understanding the genetic basis of ASD has been substantial in recent years, with the development of microarray technologies allowing the identification of copy number variants associated with the disorder [1] and massively-parallel sequencing focused on protein-coding exons allowing insights into smaller mutational events disrupting gene function [2,3]. The emerging picture is of rare rather than common genetic variants mediating most of the risk [4]. Less progress has been made in understanding
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