Biomedical subjects

Euan A Ashley

Publications and source records attributed to Euan A Ashley.

6 recordsLinked to original sources

PubMed2026

Population-scale detection of methylation outliers from long-read genome sequencing.

BACKGROUND: Aberrant DNA methylation can mediate the functional effects of rare genetic variation and contribute to imprinting disorders, repeat expansion diseases, and other pathogenic regulatory mechanisms. Long-read sequencing technologies now enable genome-wide detection of CpG methylation alongside genetic variation from a single assay. However, methods for systematic identification and interpretation of methylation outliers from long-read sequencing data remain limited. METHODS: We developed METAFORA, a computational workflow for detecting methylation outlier regions from PacBio and Oxford Nanopore long-read sequencing data. METAFORA constructs population-level methylation references, segments the genome into correlated CpG blocks, infers technical and biological sources of variation through hidden factor estimation, models uncertainty due to variable depth sequencing, and computes covariate-adjusted methylation outlier scores for individual samples. We applied METAFORA across large long-read sequencing cohorts and integrated methylation outliers with multi-omic data. METAFORA is implemented as a snakemake workflow available at https://github.com/tjense25/METAFORA. RESULTS: METAFORA identified methylation outlier regions associated with rare structural variants, tandem repeat expansions, and imprinting abnormalities. We found outlier regions were enriched for molecular outliers across transcriptomic and chromatin accessibility datasets, supporting their functional relevance in gene regulation. In a representative case, METAFORA identified an imprinting defect affecting the GNAS locus associated with an STX16 deletion. CONCLUSIONS: METAFORA enables scalable detection and interpretation of methylation outliers from long-read sequencing data and provides a framework for integrating epigenetic outliers with genomic and multi-omic analyses. These approaches may improve interpretation of rare regulatory variation and support discovery of clinically relevant epigenetic abnormalities in genomic medicine.

DNA methylation↗

PubMed2026

Colocalization and functional analyses identify GBE1 as a gene linking muscle strength and cardiometabolic fitness.

Handgrip strength is a proxy for muscular fitness, an indicator for general health status, and is associated with cardiometabolic health. The mechanisms connecting handgrip strength to skeletal muscle function are incompletely understood. We applied integrated linkage-disequilibrium-adjusted colocalization analysis of genome-wide association study summary statistics for handgrip strength, combined with expression and splicing quantitative trait loci from skeletal muscle, and identified glycogen branching enzyme 1 (GBE1) as a candidate gene for handgrip strength. CRISPR-interference knockdown of GBE1 in immortalized human skeletal muscle cells (HMCL-7304) demonstrated decreased glycogen content and accumulation of polyglucosan bodies. Knockdown of GBE1 led to increased oxygen consumption rate, oxidative stress, and changes in mitochondrial morphology. Transcriptomic profiling of GBE1 knockdown cells identified upregulation of the human superoxide dismutase 2 and enrichment of pathways related to muscle contraction and oxidative stress responses. These functional genomic analyses prioritize GBE1 as a muscle-relevant candidate gene for handgrip strength and provide mechanistic insights to muscle fitness.NEW & NOTEWORTHY Colocalization of genome-wide association study (GWAS) loci with quantitative trait loci (QTL) in skeletal muscle tissue identified GBE1 as a candidate for handgrip strength. Cellular phenotypes with GBE1 knockdown in immortalized human skeletal muscle cells include decreased glycogen content, accumulation of polyglucosan bodies, changes in mitochondrial function and morphology, and increased expression of reactive oxygen species (ROS) scavengers. Transcriptomic changes suggest a role for GBE1 in muscle contraction and oxidative stress-mediated responses.

Humans↗

PubMed2026

Social Determinants of Health and Clinical Outcomes in Hypertrophic Cardiomyopathy.

IMPORTANCE: Area-based indicators of social determinants of health (SDOH) are associated with higher risk for acquired heart disease, but their impact on conditions with a strong genetic etiology, such as hypertrophic cardiomyopathy (HCM), is not well understood. OBJECTIVE: To determine the association of area-based SDOH with clinical outcomes in patients with HCM. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective cohort study was conducted among US adult patients with HCM from 5 sites in the Sarcomeric Human Cardiomyopathy Registry (a multicenter prospective registry of patients with HCM) who were followed up for a median (IQR) period of 2.15 (0.15-5.82) years. Data were entered from 2015 to March 2024, and data analysis was completed from March 2024 to June 2025. EXPOSURES: Patients' residential addresses were geocoded at the zip code level and linked to the American Communities Survey to estimate area-based (1) median household income and (2) social deprivation index (SDI), which ranges from 0 to 100, with higher scores indicating a more deprived area. MAIN OUTCOMES AND MEASURES: Multivariate models, adjusting for age at diagnosis, body mass index, hypertension, and sex, were used to estimate the independent association of area-based median household income and SDI with heart failure (HF), ventricular arrhythmias (VA), and an overall composite outcome (VA, HF, atrial fibrillation, stroke, and death). RESULTS: Among 4431 US adult patients with HCM, median (IQR) age at HCM diagnosis was 51.3 (38.9-61.6) years, and 1862 patients (42.0%) were female. Median (IQR) area-based household income was $80 000 ($60 000-$110 000), and median (IQR) SDI was 25 (10-55). Adjusted hazard ratios comparing the lowest income group to the highest income group were 2.07 (95% CI, 1.77-2.42; P < .001) for HF, 1.31 (95% CI, 0.97-1.78; P = .08) for VA, and 1.52 (95% CI, 1.36-1.69; P < .001) for the overall composite outcome. Adjusted hazard ratios comparing the highest SDI (ie, more deprived) group to the lowest SDI group were 1.48 (95% CI, 1.29-1.70; P < .001) for HF, 1.55 (95% CI, 1.15-2.09; P = .004) for VA, and 1.36 (95% CI, 1.22-1.50; P < .001) for the overall composite outcome. CONCLUSIONS AND RELEVANCE: In this multicenter cohort study, residing in an area with lower median household income or worse SDI were each independently associated with adverse clinical outcomes in patients with HCM. These findings suggest that despite the genetically determined nature of HCM, place of residence is associated with patient outcomes.

Humans↗

PubMed2025

Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.

Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as 'variants of uncertain significance'. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale.

Humans↗

PubMed2025

Sustainability in translational genomics research with undiagnosed patients: What is it, why do we need it, and how do we do it?

PURPOSE: Genomics research enrolling undiagnosed patients can provide answers for one-third of participants, and more can be diagnosed through future reanalysis. The long-term value for participants has raised questions of the sustainability of these studies, but the meaning, goals, and best practices for sustainability remain unclear. METHODS: We conducted semistructured interviews with researchers leading studies enrolling undiagnosed patients in the United States and Canada and used thematic content analysis to summarize key themes. RESULTS: Researchers lacked consensus regarding what sustainability was actually intended to sustain, variably referencing study procedures, personnel, data access, and participant recontact. However, the primary driver of sustainability was widely shared as the perceived obligation to continue to search for answers for undiagnosed participants. Proposed sustainability strategies included diversifying funding sources, developing centralized data infrastructure, and building collaborations across disciplines and institutions. Researchers also emphasized the need to address ethical concerns, to integrate research with clinical care, and for leadership from research funders to guide these efforts. CONCLUSION: Although genomics researchers perceived continued obligations to undiagnosed participants, they also lacked a shared understanding of the goals of sustainability and called for coordinated efforts to develop centralized infrastructure that integrated research and clinical care.

Humans↗

PubMed2024

Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder.

PURPOSE: The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in 4 siblings. METHODS: We identified 5 individuals from 3 unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort. RESULTS: These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA sequencing and metabolomic data sets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation. CONCLUSION: Our data shed light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.

Humans↗