The Epigenetics of Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) comprises of a range of neurodevelopmental disorders characterised by social/communication deficits as well as repetitive/restrictive interests or behaviours. Currently, the exact causes of ASD symptomology is far from being understood. This is, in part, due to the complex and multifactorial nature of the disorder.

Despite such complexities significant progress to understanding the disorder has been made over the past few decades. Currently, it is speculated that a combination of genetic susceptibility (such as possessing rare or common mutations/variations in one’s DNA sequence) and/or prenatal/perinatal exposure to environmental risk factors (such as chemical toxins, maternal infection during gestation or hypoxia at birth) may be culpable.

But, genetics or environmental factors alone do not provide the entire picture. In fact, quantitative genetic methodologies highlight the possible role of non-sequence-based variations in the casual mechanisms to ASD. This may be partly explained by epigenetics.

For example, although identical twins share 100% of their DNA, as well as the majority of their prenatal/postnatal environment (particularly in regard to the pervading factors associated with ASD) there is notable disparity at both symptom level as well as, although rarely, overall diagnostic status. One twin may have severe social deficits while the other identical twin’s social deficits may be at a moderate level.

In a yet to be published study presented at the international INSAR2019 conference in Montreal Canada, a team of researchers explained the findings from their quantitative analysis on autistic trait (i.e. autism-like behaviours witnessed across the general population) severity differences between 347 identical twin pairs with and without ASD diagnosis1. Findings indicated inter-twin differences of ASD trait severity to be more substantial for pairs with a diagnosis (as opposed to twin pairs without any ASD diagnosis). ASD is considered to be a continuous spectrum of symptom severity, with those in the general population at the upper end of the spectrum to receive a diagnosis. Thus, as disparity was only demonstrated in those with a diagnosis, authors speculated the variability in such measured ASD traits are not down to the heritability of the disorder, but other factors that may contribute. One such factor may be between-twin differences in epigenetic profiles.

Over the past decade, there has been growing evidence for the role of epigenetic mechanisms in ASD. Notably, pathological accounts associate ASD with dysregulated brain development – a process that is underpinned by epigenetic regulation2. In fact, syndromic cases of ASD – that is, the 25% of individuals with an autism diagnosis whose symptoms are secondary to a known genetic disorder3 – demonstrate the possible role of epigenetic mechanisms in ASD. Syndromes such as Fragile X, Prader-Willi, Angelman, Rett, and Turner are a few in a long list of conditions where autism symptoms are commonly present. From this list, each disorder is also known to have core epigenetic involvement4. Take Rett Syndrome, a neurological, predominantly female-affecting disorder characterised by wrist wringing, progressive loss of social/language skills and compromised brain function. Rett Syndrome is caused by genetic mutations reducing the functioning of the X Chromosome protein MECP25. MECP2 is a key epigenetic modulator in the brain; binding to methylated DNA to control expression and chromatin architecture of a number of genes involved in neurodevelopment.

Idiopathic cases of ASD are a little more complicated than the above-mentioned syndromic cases. Idiopathic cases of ASD have no known underlying cause for the disorder. Nonetheless, researchers have begun attempts to unpick the epigenetic signature unique to individuals with an idiopathic ASD diagnosis. In a recent meta-analysis of peripheral blood samples, epigenome-wide investigations pinpointed 55 differentially methylated sites that were associated with ASD6.  Corroborating this, an investigation with identical twin pairs identified numerous differentially methylated regions associated between people with and without an ASD diagnosis, as well as between twin pairs discordant for ASD-related traits.  Not only this, but the regions found to be differentially methylated were often those housing genes associated with ASD7.

And it’s not only methylation that seems to be playing an epigenetic role in ASD. Chromatin remodeling and miRNA have been found to be implicated in ASD. Using human post-mortem samples, an international team of collaborating researchers found differential acetylation on histone H3 (specifically H3K27ac) in people with ASD8. As H3K27ac is an active enhancer marker, variations in acetylation will result in differential activation of transcription of a number of genes.

Another example, demonstrated in a separate study, is the differential expression of miRNA found in ASD cases compared to controls. Eight in peripheral (outside the brain) blood serum miRNAs were found to be markedly up- or down-regulated in individuals with an ASD diagnosis. Further investigations also confirmed these miRNAs to be involved in the expression of genes important for central nervous system development9. But both these studies were preliminary with small sample sizes investigation and further research is needed to confirm both the findings and potential application of the results.

As highlighted by the two major subtypes of ASD (syndromic and idiopathic), ASD is highly heterogenous. This means from person to person, different combinations of multiple casual factors may contribute to the manifestation of differing combinations/severity of symptoms. This muddies the water, so to speak, where research is concerned. Thus, one person’s epigenetic profile may be entirely different to another person’s profile – yet both may have a diagnosis of ASD. Along with genetic profiling, epigenetic profiling may provide the key to sub-grouping people with ASD for the ultimate goal of facilitating more targeted therapy strategies to help improve welling being if/when needed by the individual.


  1. Constantino, J. (2019). On the Nature of ‘Discordance’ in Monozygotic Twin Pairs with and without Autism–a Quantitative Trait Analysis. (2019).
  2. Spiers, H. et al. Methylomic trajectories across human fetal brain development. Genome Res. (2015).
  3. Wiśniowiecka-Kowalnik, B. & Nowakowska, B. A. Genetics and epigenetics of autism spectrum disorder—current evidence in the field. Journal of Applied Genetics (2019).
  4. Persico, A. M. & Bourgeron, T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends in Neurosciences 29, 349–358 (2006).
  5. Maheshwari, N., Christodoulou, J. & Percy, A. Rett syndrome. Anasthesiol. und Intensivmed. (2018).
  6. Andrews, S. V. et al. Case-control meta-analysis of blood DNA methylation and autism spectrum disorder. Mol. Autism (2018).
  7. Wong, C. C. Y. et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol. Psychiatry (2014).
  8. Sun, W. et al. Histone Acetylome-wide Association Study of Autism Spectrum Disorder. Cell (2016).
  9. Kichukova, T. M., Popov, N. T., Ivanov, I. S. & Vachev, T. I. Profiling of Circulating Serum MicroRNAs in Children with Autism Spectrum Disorder using Stem-loop qRT-PCR Assay. Folia Med. (Plovdiv). (2017).

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About Laurel Fish 2 Articles
Laurel Fish is an aspiring researcher currently working as a research assistant at the Centre for Brain and Cognitive Development, Birkbeck University of London. Having completed an Msc in developmental neurobiology at King’s College London, Laurel has a passion for research investigating early brain development and neurodevelopmental disorders. When not in the lab, you can find Laurel practicing yoga, editing her photography or globe-trotting to lands near and far.


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