The Role of Epigenetic Change in Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by problems with social communication, social interaction, and repetitive or restricted behaviors. ASD are comorbid with other disorders including attention deficit hyperactivity disorder, epilepsy, Rett syndrome, and Fragile X syndrome. Neither the genetic nor the environmental components have been characterized well enough to aid diagnosis or treatment of non-syndromic ASD. However, genome-wide association studies have amassed evidence suggesting involvement of hundreds of genes and a variety of associated genetic pathways. Recently, investigators have turned to epigenetics, a prime mediator of environmental effects on genomes and phenotype, to characterize changes in ASD that constitute a molecular level on top of DNA sequence. Though in their infancy, such studies have the potential to increase our understanding of the etiology of ASD and may assist in the development of biomarkers for its prediction, diagnosis, prognosis, and eventually in its prevention and intervention. This review focuses on the first few epigenome-wide association studies of ASD and discusses future directions.

Keywords: autism spectrum disorders; epigenetics; epigenomics; gene expression; methylation.

Figure 1

Diagrammatic representation of how genetic and epigenetic changes combine and interact in the etiology of ASD as summarized in the text. Epigenetic load (from prenatal environment and stochastic variation) and genetic load (from familial and de novo variation) interact to compromise neurodevelopmental, immune, oxidative stress, and mitochondrial pathways identified through studies of ASD genetics, physiology, expression, and/or methylation. We have highlighted in gray the putative involvement of specific genes mentioned in this review for which evidence has come from candidate and genome-wide studies. Examples of genes implicated in epigenetic load for ASD are ZFP57 and MECP2. In addition, sequence variants of genes involved in the control of expression such as ADNP, ASH1L, CHD8, and ARID1B (not shown), will induce epigenetic changes within genes that they regulate. Evidence has come from studies of epigenetics and gene expression for the dysregulation of OXTR, GAD1, RELN, EN2, and ENO2 during neurodevelopment in ASD. Further interactions will occur between specific genes and specific prenatal environments. Over a certain threshold of genetic and epigenetic dysfunction, development is decanalized and neurodevelopment disrupted. This includes defects in synaptic function, connectivity, and morphogenesis and would lead to abnormal brain maturation, neural circuity dysfunction, characteristic endophenotypes of ASD. Further, postnatal environments may also contribute to severity of symptoms.