Genome-wide DNA methylation patterns in Autism Spectrum Disorder and mitochondrial function

Abstract

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by 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. Epigenetic mechanisms, particularly DNA methylation, have been associated with ASD. The vast majority of ASD molecular research has focused on Northern European populations, with a paucity of data from Africa. This study examines genome-wide DNA methylation patterns in a novel cohort of South African children with ASD and matched, unrelated controls. We performed a whole-genome DNA methylation screen using the Illumina 450K Human Methylation Array. We identify differentially methylated loci associated with ASD across 898 genes (p-value ≤ 0.05). Using a pathway analysis framework, we find nine enriched canonical pathways implicating 32 of the significant genes in our ASD cohort. These pathways converge on two crucial biological processes: mitochondrial metabolism and protein ubiquitination, both hallmarks of mitochondrial function. The involvement of mitochondrial function in ASD aetiology is in line with the recently reported transcriptomic dysregulation associated with the disorder. The differentially methylated genes in our cohort overlap with the gene co-expression modules identified in brain tissue from five major neurological disorders, including ASD. We find significant enrichment of three gene modules, two of which are classified as Mitochondrial and were significantly downregulated in ASD brains. Furthermore, we find significant overlap between differentially methylated and differentially expressed genes from our dataset with a RNA seq dataset from ASD brain tissue. This overlap is particularly significant across the Occipital brain region (padj= 0.0002) which has known association to ASD. Our differential methylation data recapitulate the expression differences of genes and co-expression module functions observed in ASD brain tissue which is consistent with a central role for DNA-methylation leading to mitochondrial dysfunction in the aetiology of ASD.

Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits

“…Mitochondrial genes have been reported to be differentially expressed in the cerebral cortex of ASD patients and strongly correlated with genes associated with synaptic transmission (Schwede et al, 2018), and in SCZ, disruptions in mitochondria have been found in different brain regions, cell types, and subcellular locations (Konradi and Ö ngü r, 2017). Recently, a human whole-genome methylation study revealed that two crucial biological processes, mitochondrial metabolism and protein ubiquitination, are associated with ASD brains (Stathopoulos et al, 2018). In agreement, a genome-wide association study (GWAS) showed significant enrichment for ASD-and SCZ-associated common variants in genes that regulate synapse and mitochondrial homeostasis (Gandal et al, 2018).…”

Mitochondrial metabolism and DNA methylation: a review of the interaction between two genomes

“…Alterations in DNAm can additionally be found in genes associated with oxidative phosphorylation (OXPHOS) in disease or with age. Such is the case in human patients with autism spectrum disorder (ASD) presenting differences in methylation of the genes encoding for complex I, such as NDUFA4 , NDUFB2 , NDUFB4 and NDUFB6 , complex III, like UQCRC2 , and complex IV, for instance COX7B [ 38 ]. Likewise, complex IV methylation alterations are also seen in non-diseased elderly human muscle tissue [ 39 ] and in laboratory high fat diet-induced insulin resistance rats [ 40 ], in the genes COX7A1 and Cox5a , respectively.…”

“…Recent studies have started to focus on addressing concerns of measuring mtDNA methylation raised in a number of investigations [ 38 – 41 ]. New methodologies have been presented which are specifically adapted to mitochondrial genomes to improve bisulfite conversion of mtDNA [ 47 ], and adapted to the analysis and methylation calling for this particular genome [ 15 ], yet do still acknowledge the limitations of some of these adaptations.…”