Differential Methylation of Metabolic Mitochondrial Pathways in a South African Autism Cohort

Poster Presentation
Friday, May 11, 2018: 5:30 PM-7:00 PM
Hall Grote Zaal (de Doelen ICC Rotterdam)
S. Stathopoulos1, A. Nell1, R. Gaujoux2 and C. O'Ryan1, (1)Molecular and Cell Biology, University of Cape Town, Cape Town, South Africa, (2)Cytoreason, Tel Aviv, Israel

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by great phenotypic heterogeneity and overlapping co-morbidities. The genetic architecture of ASD is complex, with 100’s of risk genes cumulatively contributing to the aetiology of ASD. Increasingly, recent findings support a role for epigenetic mechanisms in ASD, with DNA methylation being associated with the disorder.


We investigate whole-genome methylation patterns in a cohort of South African children. Differentially methylated genes are analysed to identify biologically relevant pathways. We correlate differential methylation from the epigenome-wide methylation assay with quantitative methylation and qPCR assays of candidate differentially methylated genes in both the discovery and replication cohorts.


South African boys with ASD and boys with typical developmental profile (6 - 11 years old) were recruited. All participants were assessed using the Autism Diagnostic Observation Schedule-2, ADOS-2. DNA and RNA were extracted from study participants using buccal cells. We performed a whole-genome DNA methylation screen using Illumina 450K Human Methylation Array. Differentially methylated loci associated with ASD were assessed using a pathway-analysis approach. We validate our top differentially methylated gene from the whole epigenome assay, the stomatin-like protein 2 (STOML2) gene, using a quantitative pyrosequencing assay for DNA methylation, as well as a qPCR approach to quantify mRNA.


We identified over 900 differentially methylated genes (p-value ≤ 0.05) associated with ASD. Pathway analysis revealed canonical Metabolic, Mitochondrial and Autophagy pathways as being significantly enriched in our cohort. We correlate differential methylation patterns of STOML2 from the epigenome-wide assay, with a quantitate methylation measure, DNA pyrosequencing, as well RNA expression levels. The quantitative data supports a role for differential methylation in perturbating mitochondrial pathways in ASD individuals.


This study is the first to investigate whole-epigenome profiles of DNA methylation in a South African cohort of children with ASD. We find that methylation patterns differ significantly between ASD and typically developing children at a large number of genes which converge on mitochondrial dysfuntion. We validate differential methylation and transcription levels of our top gene, STOML2, which is central to mitochondrial stress and the accumulation of reactive oxygen species. Our results suport a central role for mitochondrail function in ASD aetiology. As there are a number of pre-existing therapeutic options already in use for mitochondrial dysfunction, our results have important implications for re-examining exsiting therapeutic treatment of ASD symptomology.