Biology subjects

O'Ryan, C.

Publications and source records attributed to O'Ryan, C..

3 recordsLinked to original sources

bioRxiv2022

Molecular autism research in Africa: a scoping review comparing publication outputs to Brazil, India, the UK, and the USA.

The increased awareness of autism spectrum disorders (ASD) is accompanied by burgeoning ASD research, and concerted research efforts are trying to elucidate the molecular ASD aetiology. However, much of this research is concentrated in the Global North, with recent reviews of research in Sub-Saharan Africa (SSA) highlighting the significant shortage of ASD publications from this region. The most limited focus area was molecular research with only two molecular studies ever published from SSA, both being from South Africa (SA). We examine the molecular ASD research publications from 2016 to 2021 from all African countries, with a special focus on SA. The SSA publications are compared to Brazil and India, two non-African, low-to-middle-income countries (LMICs), and to the UK and USA, two high-income countries (HICs). There were 228 publications across all regions of interest; only three publications were from SA. Brazil (n=29) and India (n=27) had almost 10 times more publications than SA. The HICs had more publications than the LMICs, with the UK (n=62) and the USA (n=74) having approximately 20 to 25 times more publications than SA, respectively. Given that SA has substantial research capacity as demonstrated by its recent research on SARS-CoV-2, we explore potential reasons for this deficit in molecular ASD publications from SA. We compare mental health research outputs, GDP per capita, research and development expenditure, and the number of psychiatrists and child psychiatrists per 100,000 people across all regions. The UK and the USA had significantly higher numbers for all these indicators, consistent with their higher publication output. Among the LMICs, SA can potentially produce more molecular ASD research, however, there are numerous barriers that need to be addressed to facilitate increased research capacity. These include cultural stigmas, challenges in accessing mental healthcare, shortages of specialists in the public sector, and the unreliability of ASD diagnostic tools across the 11 official SA languages. The unique genetic architecture of African populations presents an untapped reservoir for finding novel genetic loci associated with ASD. Therefore, addressing the disparity in molecular ASD research between the Global North and SSA is integral to global advancements in ASD research.

molecular biology↗

bioRxiv2021

DNA methylation of PGC-1α is associated with elevated mtDNA copy number and altered urinary metabolites in Autism Spectrum Disorder

BackgroundAutism Spectrum Disorder (ASD) is a complex disorder that is underpinned by numerous dysregulated biological pathways, including canonical mitochondrial pathways. Epigenetic mechanisms contribute to this dysregulation and DNA methylation is an important factor in the aetiology of ASD. We examined the relationship between DNA methylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1), an essential transcriptional regulator of mitochondrial homeostasis, and mitochondrial dysfunction in an ASD cohort of South African children. ResultsUsing targeted Next Generation bisulfite sequencing, we found 12 highly variable CpG sites in PGC-1 that were significantly differentially methylated (p<0.05) between ASD (n = 55) and controls (n = 44). In ASD, eight CpG sites were hypermethylated in the PGC-1 promotor with a putative binding site for CAMP response binding element 1 (CREB1) spanning one of these CpG sites (p = 1 x 10-6). Mitochondrial DNA (mtDNA) copy number, a marker of mitochondrial function, was elevated (p = 0.002) in ASD compared to controls and correlated significantly with DNA methylation at the PGC-1 promoter. There was a positive correlation between methylation at PGC-1 at CpG#1 and mtDNA copy number (Spearmans r = 0.2, n = 49, p = 0.04) in ASD, but a negative correlation between methylation at PGC-1 at CpG#4 promoter and mtDNA copy number in controls (Spearmans r = -0.4, n = 42, p = 0.045). While there was no relationship between mtDNA deletions and PGC-1 methylation in ASD, mtDNA deletions correlated negatively with methylation at PGC-1 at CpG#4 (Spearmans r = -0.4, n = 42, p = 0.032) in controls. Furthermore, levels of urinary organic acids associated with mitochondrial dysfunction correlated significantly (p<0.05) with DNA methylation at PGC-1 CpG#1 and mtDNA copy number in ASD (n= 20) and controls (n= 13) with many of these metabolites involved in altered redox homeostasis and neuroendocrinology. ConclusionsThese data show an association between PGC-1 promoter methylation, elevated mtDNA copy number and metabolomic evidence of mitochondrial dysfunction in ASD. This highlights an unexplored link between DNA methylation and mitochondrial dysfunction in ASD.

neuroscience↗

bioRxiv2018

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

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by phenotypic heterogeneity and overlapping co-morbidities. The genetic architecture of ASD is complex, with 100s 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.

genetics↗