Biology subjects

Garton, F.

Publications and source records attributed to Garton, F..

5 recordsLinked to original sources

bioRxiv2026

Sex-dependent DNA methylation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) shows well-established sex differences in incidence, age at onset and progression, but their biological basis is unclear. We hypothesised that the DNA methylation changes associated with ALS differ between the sexes, which would point to sex-specific disease processes. To test this, we performed a blood-based epigenome-wide association meta-analysis of ALS cases and controls from Project MinE, an international ALS genomics consortium, and an independent Australian cohort, comprising 8,946 individuals after quality control (5,129 males and 3,817 females; 8,942 with complete covariates in the primary models). We analysed 781,648 autosomal CpGs using complementary sex-stratified case-control models and an ALS-by-sex interaction model that directly tested whether ALS-associated methylation effects differed by sex. Sex-stratified analyses identified no genome-wide significant differences between male and female ALS effects. In contrast, interaction testing identified seven robust sex-dependent ALS-associated differentially methylated positions (P < 9 x 10-8), mapping to KCNQ1, ADPRH, HLA-F, GHRLOS, IRF5, RAD51B and one intergenic region. The strongest signal was at KCNQ1 (P = 3.1 x 10-9). Six of the seven remained genome-wide significant in a four-stratum sensitivity analysis, and none was detected in previous conventional ALS or population sex-associated methylation analyses. Together, these findings suggest a distinct sex-conditional component of the ALS blood methylome, implicating immune, metabolic and ion-channel loci and providing new candidates for investigating biological heterogeneity between males and females with ALS.

genomics↗

bioRxiv2024

Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.

genomics↗

bioRxiv2023

Ggnbp2 regulates synaptic development and autophagy in motor neurons

AbstractGenome-wide association studies (GWAS) have identified numerous candidate ALS risk variants, but their cellular functions are often unknown. Recent studies have identified a variant of GGNBP2 that results in increased expression. To better understand how this gene might contribute to disease, we investigated the function of Drosophila Ggnbp2 (dGgnbp2) in motor neurons. Loss of function studies showed that dGgnbp2 is required for motor neuron synaptic development. A human transgene completely rescued these phenotypes indicating that the gene is functionally conserved between humans and flies. Overexpression of dGgnbp2 caused severe locomotor defects in adult flies, consistent with ALS pathology. At the cellular level, dGgnbp2 regulated autophagy, a process commonly defective in ALS. Both overexpression and removal of dGgnbp2 reduced levels of the phosphorylated lipid, PI(3)P, an essential component of autophagosomes. Our study provides strong evidence that Ggnbp2 functions in motor neurons to regulate a cellular process commonly defective in ALS. TeaserThis study investigated the function of the ALS risk variant GGNBP2, in flies, and showed that it regulates autophagy in motor neurons.

neuroscience↗

bioRxiv2023

Arylamine N-acetyltransferase-1 reveals a subpopulation of ALS patients with altered metabolic capacity

Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease characterised by metabolic changes at onset and throughout disease progression. Here, we investigate the role of arylamine N-acetyltransferase 1 (NAT1), a cytosolic protein associated with mitochondrial function, in ALS. We demonstrate that expression of the murine homolog (mNat2) increases in skeletal muscle of SODG93A mice, but not control animals, at onset of symptoms and remains elevated until end stage of the disease. Measurement of mitochondrial respiration in peripheral blood mononuclear cells of patients with ALS identified patient sub-populations with low and high metabolic potential, which was strongly associated with NAT1 activity. Those patients with high NAT1 activity had elevated basal respiration, ATP production, mitochondrial reserve, and aerobic glycolysis. NAT1 predicted increased whole body metabolic index, which may be clinically significant as these patients show increased functional decline and shorter survival. NAT1 may be a novel target in those patients with elevated activity.

biochemistry↗

bioRxiv2020

Estimating the rate of cell type degeneration from epigenetic sequencing of cell-free DNA

Circulating cell-free DNA (cfDNA) in the bloodstream originates from dying cells and is a promising non-invasive biomarker for cell death. Here, we develop a method to accurately estimate the relative abundances of cell types contributing to cfDNA. We leverage the distinct DNA methylation profile of each cell type throughout the body. Decomposing the cfDNA mixture is difficult, as fragments from relevant cell types may only be present in a small amount. We propose an algorithm, CelFiE, that estimates cell type proportion from both whole genome cfDNA input and reference data. CelFiE accommodates low coverage data, does not rely on CpG site curation, and estimates contributions from multiple unknown cell types that are not available in reference data. In simulations we show that CelFiE can accurately estimate known and unknown cell type of origin of cfDNA mixtures in low coverage and noisy data. Simulations also demonstrate that we can effectively estimate cfDNA originating from rare cell types composing less than 0.01% of the total cfDNA. To validate CelFiE, we use a positive control: cfDNA extracted from pregnant and non-pregnant women. CelFiE estimates a large placenta component specifically in pregnant women (p = 9.1 x 10-5). Finally, we use CelFiE to decompose cfDNA from ALS patients and age matched controls. We find increased cfDNA concentrations in ALS patients (p = 3.0 x 10-3). Specifically, CelFiE estimates increased skeletal muscle component in the cfDNA of ALS patients (p = 2.6 x 10-3), which is consistent with muscle impairment characterizing ALS. Quantification of skeletal muscle death in ALS is novel, and overall suggests that CelFiE may be a useful tool for biomarker discovery and monitoring of disease progression.

genomics↗