Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits

C C Y Wong, E L Meaburn, A Ronald, T S Price, A R Jeffries, L C Schalkwyk, R Plomin, J Mill, C C Y Wong, E L Meaburn, A Ronald, T S Price, A R Jeffries, L C Schalkwyk, R Plomin, J Mill

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.

Figures

Figure 1
Figure 1
(a) A significantly (P<2.2E−16) higher number of CpG sites with a large average within-twin β differences was observed in autism spectrum disorder (ASD)-discordant monozygotic (MZ) twin pairs compared with unaffected twin pairs (that is, concordant for low Childhood Autism Symptom Test (CAST) score). (b) Absolute mean Δβ of the top 50 differentially methylated CpG sites in ASD-discordant MZ twin pairs and in unaffected MZ twin pairs.
Figure 2
Figure 2
DNA methylation differences (Δβ; autism spectrum disorder (ASD) twin minus well twin) for the top 10 ASD-associated differentially methylated CpG sites in six ASD-discordant monozygotic (MZ) twin pairs.
Figure 3
Figure 3
(a) The top 10 CpG sites showing the most significant correlation with total Childhood Autism Symptom Test (CAST) score. Each circle represents a sample. For some loci, the high correlations are influenced by extreme DNA methylation and CAST scores from a single pair of autism spectrum disorder (ASD)-concordant twins (denoted as blue triangles). (b) Significant correlation between P2RY11 and NRXN1 DNA methylation and quantitative autistic trait scores remains when the extreme twin pair was excluded. Solid and dashed lines represent results from correlation analysis including and excluding the extreme twin pair, respectively.

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