Abstract
BackgroundThe etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained. Given the unexplained risk and recent evidence supporting a role for epigenetic mechanisms in the development of autism, we explored the role of CpG and CpH (H = A, C, or T) methylation within the autism-affected cortical brain tissue.MethodsReduced representation bisulfite sequencing (RRBS) was completed, and analysis was carried out in 63 post-mortem cortical brain samples (Brodmann area 19) from 29 autism-affected and 34 control individuals. Analyses to identify single sites that were differentially methylated and to identify any global methylation alterations at either CpG or CpH sites throughout the genome were carried out.ResultsWe report that while no individual site or region of methylation was significantly associated with autism after multi-test correction, methylated CpH dinucleotides were markedly enriched in autism-affected brains (~2-fold enrichment at p < 0.05 cutoff, p = 0.002).ConclusionsThese results further implicate epigenetic alterations in pathobiological mechanisms that underlie autism.
Highlights
The etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained
To gain a more complete picture of altered DNA methylation (DNAm) in autism, we carried out Reduced representation bisulfite sequencing (RRBS) in 71 post-mortem cortical brain samples (BA19) at single nucleotide resolution with a quantitative measurement of DNAm across CpG-dense regions of the genome [23]
Samples with altered patterns of global methylation patterns, as determined by surrogate variable analysis (SVA), were identified and removed from analysis (N = 4). While this has been demonstrated to be a sound method for sample outlier removal in RNA-sequencing data previously [14], we ensured that these samples should, be removed in this RRBS experiment by testing for the proportion of previously identified brain meQTLs detected after the iterative removal of each detected sample outlier
Summary
The etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained. Given the unexplained risk and recent evidence supporting a role for epigenetic mechanisms in the development of autism, we explored the role of CpG and CpH (H = A, C, or T) methylation within the autism-affected cortical brain tissue. Autism is a heritable neurodevelopmental disorder affecting one in 68 individuals in the USA [1]. Recent genetic studies have identified a handful of genes that contribute to autism [2], and gene expression studies have begun to unravel how altered gene expression manifests within the autistic brain [3, 4]; the majority of risk remains unexplained. In addition to genetic causes, epigenetic mechanisms have been proposed to play an important role in the development of the disorder. Deficiencies in DNA methylation (DNAm), historically studied in CpG islands in gene promoters as
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