Abstract
Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behaviour. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular aetiology of ASD, we quantified genome-wide patterns of DNA methylation in 223 post-mortem tissues samples isolated from three brain regions [prefrontal cortex, temporal cortex and cerebellum (CB)] dissected from 43 ASD patients and 38 non-psychiatric control donors. We identified widespread differences in DNA methylation associated with idiopathic ASD (iASD), with consistent signals in both cortical regions that were distinct to those observed in the CB. Individuals carrying a duplication on chromosome 15q (dup15q), representing a genetically defined subtype of ASD, were characterized by striking differences in DNA methylationacross a discrete domain spanning an imprinted gene cluster within the duplicated region. In addition to the dramatic cis-effects on DNA methylation observed in dup15q carriers, we identified convergent methylomic signatures associated with both iASD and dup15q, reflecting the findings from previous studies of gene expression and H3K27ac. Cortical co-methylation network analysis identified a number of co-methylated modules significantly associated with ASD that are enriched for genomic regions annotated to genes involved in the immune system, synaptic signalling and neuronal regulation. Our study represents the first systematic analysis of DNA methylation associated with ASD across multiple brain regions, providing novel evidence for convergent molecular signatures associated with both idiopathic and syndromic autism.
Highlights
Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social interactions and understanding, repetitive behaviour and interests and impairments in language and communication development
We quantified DNA methylation across the genome using the Illumina Infinium HumanMethylation450 BeadChip (‘450K array’) in 223 post-mortem tissue samples comprising prefrontal cortex (PFC), temporal cortex (TC) and CB dissected from 43 donors with ASD and 38 nonpsychiatric control subjects
We quantified DNA methylation in 223 postmortem tissue samples isolated from the PFC, TC and CB dissected from 43 donors with ASD and 38 non-psychiatric control subjects
Summary
Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social interactions and understanding, repetitive behaviour and interests and impairments in language and communication development. Despite the highly heterogeneous role of genetic variation in ASD, studies of transcriptional [10,11] and regulatory genomic variation [12] in post-mortem ASD brain provide evidence for a highly convergent molecular pathology, with individuals affected genetically defined subtypes of ASD sharing the core transcriptional signatures observed in idiopathic autism cases. There is increasing evidence to support a role for nonsequence-based genomic variation in the aetiology of neurodevelopmental phenotypes including ASD [13]. Despite finding evidence for ASD-associated methylomic variation, these analyses have been constrained by the analysis of small sample numbers and limited to the assessment of peripheral tissues or a single brain region [12,23,24,25,26,27,28,29]
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