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

Abstract

Autism spectrum disorder (ASD) encompasses a collection of complex neuropsychiatric disorders characterized by deficits in social functioning, communication and repetitive behavior. Building on recent studies supporting a role for developmentally moderated regulatory genomic variation in the molecular etiology of ASD, we quantified genome-wide patterns of DNA methylation in 233 post-mortem tissues samples isolated from three brain regions (prefrontal cortex, temporal cortex and cerebellum) 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 cerebellum. 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 comethylation 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.

Integrated genetic and methylomic analyses identify shared biology between autism and autistic traits

“…In contrast to the results from the peripheral tissues, we observed some degree of overlap between MWAS conducted in post-mortem brain tissues 20,23 and the SCDC MWAS.…”

“…Considering this, we investigated if there is an enrichment between the SCDC MWAS and MWAS of the postmortem autism brain. Using data from the latest post-mortem brain study 23 , we investigated concordance in effect direction between all CpG probes with P < 1x10 -4 from the cross-cortex analysis in the SCDC MWAS. 171 out of 293 CpGs had a concordant effect direction in the two datasets (P = 0.004).…”

“…DNA methylation is partly heritable 15,16 , with approximately 40% of CpG sites having a significant genetic component 17 . Previous studies have investigated autism associated methylation signatures in both peripheral tissues 14,18,19 and in the post-mortem brain [20][21][22][23] . While post-mortem brain is pertinent for a neurodevelopmental condition like autism, it is not readily accessible, and will be confounded by post-mortem effects on methylation patterns.…”

“…While post-mortem brain is pertinent for a neurodevelopmental condition like autism, it is not readily accessible, and will be confounded by post-mortem effects on methylation patterns. Studies of methylation signatures in postmortem brains in autism have replicably identified differential methylation [20][21][22][23] . Further, they have demonstrated an enrichment for differentially methylated signatures in immune system, synaptic signalling and neuronal regulation 20,21,23 .…”

“…Studies of methylation signatures in postmortem brains in autism have replicably identified differential methylation [20][21][22][23] . Further, they have demonstrated an enrichment for differentially methylated signatures in immune system, synaptic signalling and neuronal regulation 20,21,23 . In contrast, recent large-scale analysis of three different peripheral tissue datasets have not identified significantly differentially methylated CpG sites in cases compared to controls 14,19 .…”