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 diagnosis^[1]. 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 regulation^[2]. In fact, syndromic cases of ASD – that is, the 25% of individuals with an autism diagnosis whose symptoms are secondary to a known genetic disorder^[3] – 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 involvement^[4]. 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 MECP2^[5]. 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 ASD^[6].  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 ASD^[7].