Genome-Wide DNA Methylation Profiles in Post-Mortem Brains From Subjects with Autism

Background: Autism is a developmental disorder characterized by severe and sustained impairment in social interaction and communication, and restricted or stereotyped patterns of behavior and interest. This disorder is more prevalent in males than in females. Although twin studies have provided evidence for a strong genetic component for the condition and many candidate genes have been reported, the underlying genetic role and its mechanism have yet to be determined. Recently, it has been reported that genetic heritability is lower than that previously estimated, and environmental factors also have a greater influence on the development of autism. Epigenetic processes such as DNA methylation and histone modification are considered to be an interface of genetic and environmental factors. Additionally, two well-characterized epigenetic processes, parental imprinting and X chromosome inactivation, are known to be involved in several conditions that mimic autism spectrum disorders, such as  Angelman, Prader-Willi, 15q duplication, Rett and Fragile-X syndromes. This clinical evidence suggests that epigenetic processes may play an important role in the pathophysiology of autism.  Thus, we investigated genome-wide DNA methylation profiles in post-mortem brain tissue from individuals with autism.

Objectives: Drsal raphe from 6 male subjects with autism and 7 age- and sex-matched healthy control subjects.

Methods: We measured methylation levels of CpG sites in these samples using Infinium HumanMethylation450 BeadsChip.

Results: We found significantly elevated levels of methylation in 44 CpG-sites in 40 gene regions and significantly decreased levels of methylation in 37 CpG-sites in 34 gene regions in subjects with autism compared to controls. Some of these genes, such as DAB1 and GRIA1, have been implicated in autism and other developmental disorders (Fatemi et al., 2005; Ayalew et al., 2012). We subsequently examined to see whether modifications would be present especially on sex chromosome and altered levels of methylation were found in CpG-sites in chromosome X, but not in chromosome Y.

Conclusions: In this postmortem study, we found significant differences in DNA methylation profiles between the brains of autism and control subjects. The abnormal DNA methylations, especially gene regions implicated in autism and other developmental disorders, may underlie the pathophysiology of autism. Moreover, in sex chromosomes, abnormal DNA methylations only in X chromosome may account for the unequal sex ratio in autism.