An Epigenetically Distinct Subset of Children With Autism Spectrum Disorder Resulting From Differences in Blood Cell Composition.

Maryam Jangjoo,Evdokia Anagnostou,Russell Schachar,Sarah J Goodman,Elizabeth Kelley,Jennifer Crosbie,Brett Trost,Rosanna Weksberg,Sanaa Choufani,Stelios Georgiades,Stephen W Scherer,Eyal Grunebaum,Muhammad Ayub,Rob Nicolson

doi:10.3389/fneur.2021.612817

Abstract

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that often involves impaired cognition, communication difficulties and restrictive, repetitive behaviors. ASD is extremely heterogeneous both clinically and etiologically, which represents one of the greatest challenges in studying the molecular underpinnings of ASD. While hundreds of ASD-associated genes have been identified that confer varying degrees of risk, no single gene variant accounts for >1% of ASD cases. Notably, a large number of ASD-risk genes function as epigenetic regulators, indicating potential epigenetic dysregulation in ASD. As such, we compared genome-wide DNA methylation (DNAm) in the blood of children with ASD (n = 265) to samples from age- and sex-matched, neurotypical controls (n = 122) using the Illumina Infinium HumanMethylation450 arrays.Results: While DNAm patterns did not distinctly separate ASD cases from controls, our analysis identified an epigenetically unique subset of ASD cases (n = 32); these individuals exhibited significant differential methylation from both controls than the remaining ASD cases. The CpG sites at which this subset was differentially methylated mapped to known ASD risk genes that encode proteins of the nervous and immune systems. Moreover, the observed DNAm differences were attributable to altered blood cell composition, i.e., lower granulocyte proportion and granulocyte-to-lymphocyte ratio in the ASD subset, as compared to the remaining ASD cases and controls. This ASD subset did not differ from the rest of the ASD cases in the frequency or type of high-risk genomic variants.Conclusion: Within our ASD cohort, we identified a subset of individuals that exhibit differential methylation from both controls and the remaining ASD group tightly associated with shifts in immune cell type proportions. This is an important feature that should be assessed in all epigenetic studies of blood cells in ASD. This finding also builds on past reports of changes in the immune systems of children with ASD, supporting the potential role of altered immunological mechanisms in the complex pathophysiology of ASD. The discovery of significant molecular and immunological features in subgroups of individuals with ASD may allow clinicians to better stratify patients, facilitating personalized interventions and improved outcomes.

Highlights

Autism spectrum disorder (ASD) is a heritable and prevalent neurodevelopmental disorder that is usually defined by impairments in cognition, communication and social interaction as well as by restrictive and/or stereotypical repetitive behaviors [1]
Principal component analysis (PCA) run on the 400 differentially methylated sites showed a gradient of DNA methylation (DNAm) values starting from a group of mostly controls to a separate subset of ASD-affected individuals that was epigenetically distinct from both controls and remaining ASD cases (n =32; Figure 1; Table 1)
This observation was supported by hierarchical clustering of DNAm values, with this DNAm gradient going from a cluster comprised of mostly controls where the majority of differentially methylated Cytosine- phosphate- Guanine (CpG) are hypomethylated to the distinct ASD subset where the majority of these sites are hypermethylated

Summary

Introduction

Autism spectrum disorder (ASD) is a heritable and prevalent neurodevelopmental disorder that is usually defined by impairments in cognition, communication and social interaction as well as by restrictive and/or stereotypical repetitive behaviors [1]. Despite intense research efforts during the past decade, no definitive biological or clinical markers for ASD have been identified [2,3,4]. This can be partly explained by the highly heterogeneous nature of ASD, both clinically and etiologically, which represents one of the greatest challenges in studying the molecular basis of ASD. Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that often involves impaired cognition, communication difficulties and restrictive, repetitive behaviors.

Results

Discussion

Conclusion