Abstract
Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.
Highlights
Autism spectrum disorder (ASD) defines a collection of complex childhood neurodevelopmental disorders affecting B1% of the population and conferring severe lifelong disability.[1]
Within-twin patterns of DNA methylation were highly correlated across all MZ twin pairs, indicating that ASD and related traits are not associated with systemic changes in epigenetic programming
We report ASD-associated DNA methylation differences at numerous CpG sites, with some DMRs consistent across all discordant twin pairs for each diagnostic category and others specific to one or two twin pairs, or one or two autism-related traits
Summary
Autism spectrum disorder (ASD) defines a collection of complex childhood neurodevelopmental disorders affecting B1% of the population and conferring severe lifelong disability.[1]. The use of disease-discordant MZ twins represents a powerful strategy in epigenetic epidemiology because identical twins are matched for genotype, age, sex, maternal environment, population cohort effects and exposure to many shared environmental factors.[16,17] Recent studies have uncovered considerable epigenetic variation between MZ twins,[18,19,20] and DNA methylation differences have been associated with MZ twin discordance for several complex phenotypic traits, including psychosis[21] and Type 1 diabetes.[22] In ASD, Nguyen and co-workers[23] recently examined lymphoblastoid cell lines derived from peripheral blood lymphocytes collected from three ASD-discordant MZ twin pairs, reporting several ASD-associated differentially methylated loci.[23] Two loci (RORA and BCL2) reported as hypermethylated in ASD were found to be downregulated in RNA from post-mortem autism brains These findings support a role for DNA methylation in ASD and highlight the successful use of peripherally derived DNA from discordant MZ twins to identify disease-associated epigenetic changes. Received 27 November 2012; revised 21 January 2013; accepted 6 March 2013; published online 23 April 2013
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