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Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue

Wong, CCY and Smith, RG and Hannon, E and Ramaswami, G and Parikshak, NN and Assary, E and Troakes, C and Poschmann, J and Schalkwyk, LC and Sun, W and Prabhakar, S and Geschwind, DH and Mill, J (2019) 'Genome-wide DNA methylation profiling identifies convergent molecular signatures associated with idiopathic and syndromic autism in post-mortem human brain tissue.' Human Molecular Genetics, 28 (13). 2201 - 2211. ISSN 0964-6906

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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 methylation across 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.

Item Type: Article
Uncontrolled Keywords: gene expression, autistic disorder, dna methylation, genes, genome, methylation, brain, gene clusters, brain tissue, donors
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Elements
Date Deposited: 16 Oct 2019 09:33
Last Modified: 16 Oct 2019 10:15
URI: http://repository.essex.ac.uk/id/eprint/25612

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