Biology subjects

Elliott, H. R.

Publications and source records attributed to Elliott, H. R..

7 recordsLinked to original sources

bioRxiv2024

Imputed DNA methylation outperforms measured loci associations with smoking and chronological age

Multi-locus signatures of blood-based DNA methylation are well-established biomarkers for lifestyle and health outcomes. Here, we focus on two CpGs that are strongly associated with age and smoking behaviour. Imputing these loci via epigenome-wide CpGs results in stronger associations with outcomes in external datasets compared to directly measured CpGs. If extended epigenome-wide, CpG imputation could augment historic arrays and recently-released, inexpensive but lower-content arrays, thereby yielding better-powered association studies.

genetics↗

bioRxiv2022

DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood

Human height is strongly influenced by genetics but the contribution of modifiable epigenetic factors is under-explored, particularly in low and middle-income countries (LMIC). We investigated links between blood DNA methylation and child height in four LMIC cohorts (n=1927) and identified a robust association at three CpGs in the suppressor of cytokine signalling 3 (SOCS3) gene which replicated in a high-income country cohort (n=879). SOCS3 methylation (SOCS3m) - height associations were independent of genetic effects. Mendelian randomization analysis confirmed a causal effect of SOCS3m on height. In longitudinal analysis in a LMIC cohort, SOCS3m explained a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increased from birth to 21 years (2% to 18%). Childrens SOCS3m was associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirmed a regulatory effect of SOCS3m on gene expression. Our findings suggest that epigenetic modifications may play an important role in driving child height in LMIC.

genomics↗

bioRxiv2021

Characterizing the human methylome across the life course: findings from eight UK-based studies

Variation in DNA methylation (DNAm) is associated with multiple biological processes that track growth and development, ageing and age-related diseases. However, there is little understanding of what constitutes typical patterns of DNAm variation and how these patterns change across the life course. In this study, we synthesised a map of the human methylome across the life course, focussing on changes in variability and mean DNAm. Harmonizing DNAm datasets across eight longitudinal and cross-sectional UK-based studies, we meta-analysed n=13,215 blood samples from n=7,037 unique individuals from birth to 98 years of age. Changes in CpG-specific variability and means were described across the life course using a meta-regression framework. CpG-specific associations of variability or mean DNAm in relation to the likelihood of association with 100 traits linked to environmental exposures, health and disease were tested within and across ten developmental age bins across the life course. Age was linked to DNAm variability at 29,212 CpG sites. On average, we observed a 1.26 fold increase in DNAm variability per year across the life course. 33,730 CpGs displayed changes in mean DNAm, with 64% of these loci showing decreases in DNAm over time. CpG sites linked to traits were in general more variable across the life course. Our study provides, for the first time, a map of the human methylome across the life course, which is publicly accessible through a searchable online database. This resource allows researchers to query CpG-specific trajectories from birth to old age and link these to health and disease.

genetics↗

bioRxiv2020

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

Biological ageing estimators derived from DNA methylation (DNAm) data are heritable and correlate with morbidity and mortality. Leveraging DNAm and SNP data from >41,000 individuals, we identify 137 genome-wide significant loci (113 novel) from meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We report strong genetic correlations with longevity and lifestyle factors such as smoking, education, and obesity. Significant associations are observed in polygenic risk score analysis and to a lesser extent in Mendelian randomization analyses. This study illuminates the genetic architecture underlying epigenetic ageing and its shared genetic contributions with lifestyle factors and longevity.

genetics↗

bioRxiv2020

Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

BackgroundIncidence rates for melanoma and non-melanoma skin cancer (NMSC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), have been steadily increasing in all populations. Populations of European ancestry exhibit the highest rates and therefore, have been widely studied. Pigmentation characteristics are well-known risk factors for skin cancer, particularly fair skin, red hair, blue eyes and the inability to tan. Polymorphisms in established pigmentation-related genes have been associated with these traits and with an increased risk of malignancy. However, the functional relationship between genetic variation and disease is still unclear, with the exception of red hair colour variants in the melanocortin 1 receptor (MC1R) gene. ObjectivesThe aim of this study was to explore the possibility that non-coding pigmentation SNPs are associated with pigmentary traits and skin cancer via DNA methylation (DNAm). Methods and ResultsUsing a meta-GWAS of whole blood DNAm from 36 European cohorts (N=27,750; the Genetics of DNA Methylation Consortium, GoDMC), we found that 19 out of 27 pigmentation-associated SNPs distributed within 10 genes (ASIP, BNC2, IRF4, HERC2, MC1R, OCA2, SLC24A4, SLC24A5, SLC45A2, TYR) were associated with 391 DNAm sites across 30 genomic regions. We selected 25 DNAm sites for further analysis. We examined the effect of the chosen DNAm sites on pigmentation traits, sun exposure phenotypes, and skin cancer, and on gene expression in whole blood. We found an association of decreased DNAm at cg07402062 with red hair in the Avon Longitudinal Study of Parents and Children (ALSPAC), and a strong positive association of DNAm at this and correlated sites with higher expression of SPIRE2. Additionally, we investigated the association of gene expression in skin with pigmentation traits and skin cancer. The expression of ASIP, FAM83C, NCOA6, CDK10, and EXOC2 was associated with hair colour, whilst that of ASIP and CDK10 also had an effect on melanoma and BCC. ConclusionsOur results indicate that DNAm and expression of genes in the 16q24.3 and 20q11.22 regions, deserve to be further investigated as potential mediators of the relationship between genetic variants, pigmentation/sun exposure phenotypes, and some types of skin cancer.

genetics↗

bioRxiv2019

DNA hypomethylation during MSC chondrogenesis occurs predominantly at enhancer regions

SummaryRegulation of transcription occurs in a cell type specific manner by epigenetic mechanisms including DNA methylation and histone modifications. Methylation changes during stem cell differentiation may play a key role in lineage specification. We sought to characterise DNA methylation changes during chondrogenesis of mesenchymal stem cells (MSCs) in order to further our understanding of epigenetic regulation in chondrocytes. The consequences of which has potential to improve cartilage generation for tissue engineering purposes and also to provide context for observed methylation changes in cartilage diseases such as osteoarthritis. We identified significant DNA hypomethylation during chondrogenesis including changes at many key cartilage gene loci. Importantly characterisation of significant CpG loci indicated their predominant localisation to enhancer regions. Comparison with adult cartilage and other tissue methylation profiles identified chondrocyte-specific regulatory regions. Taken together we have associated methylation at many CpGs with the chondrocyte phenotype.\n\nAbstractRegulation of transcription is determined in a cell type specific manner by epigenetic mechanisms including DNA methylation and histone modifications. Methylation changes during stem cell differentiation may play a role in lineage specification. Multipotent mesenchymal stem cell (MSC) differentiation into chondrocytes not only serves as a model for chondrocyte development but also provides an important source of cartilage for tissue engineering purposes. We sought to characterise DNA methylation changes during chondrogenesis to further understanding of epigenetic regulation but to also provide context for the changes identified during disease.\n\nDNA cytosine methylation changes during human MSC differentiation into chondrocytes were measured by Infinium 450K methylation array. Methylation changes at gene loci were contrasted with gene expression changes. Chromatin states of significant methylation loci were interpreted by intersection with chondrogenesis histone modification ChlP-seq data. Chondrogenic and cartilage specific hypomethylation was utilised in order to identify a chondrocyte methylome. Articular cartilage and tissue panel DNA methylation was compared and alterations during osteoarthritis cartilage disease classified.\n\nSignificant DNA hypomethylation was identified following chondrogenic differentiation of MSCs including changes at many key cartilage gene loci. Highly upregulated genes during chondrogenesis were more likely to exhibit a reduction in DNA methylation. Characterisation of significant CpG loci indicated their predominant localisation in CpG poor regions which importantly are most likely to correspond to enhancer regions. Methylation level at certain CpGs following chondrogenesis corresponds to the level found in adult cartilage.\n\nTaken together, considerable demethylation changes to the epigenetic landscape occur during MSC chondrogenesis especially at sites marked by enhancer modifications. Comparison with other tissues, including healthy and OA cartilage, associates CpGs to the chondrocyte phenotype and provides context for changes in disease.

genomics↗

bioRxiv2018

PGP-UK: a research and citizen science hybrid project in support of personalized medicine

Molecular analyses such as whole-genome sequencing have become routine and are expected to be transformational for future healthcare and lifestyle decisions. Population-wide implementation of such analyses is, however, not without challenges, and multiple studies are ongoing to identify what these are and explore how they can be addressed. Defined as a research project, the Personal Genome Project UK (PGP-UK) is part of the global PGP network and focuses on open data sharing and citizen science to advance and accelerate personalized genomics and medicine. Here we report our findings on using an open consent recruitment protocol, active participant involvement, open access release of personal genome, methylome and transcriptome data and associated analyses, including 47 new variants predicted to affect gene function and innovative reports based on the analysis of genetic and epigenetic variants. For this pilot study, we recruited ten participants willing to actively engage as citizen scientists with the project. In addition, we introduce Genome Donation as a novel mechanism for openly sharing previously restricted data and discuss the first three donations received. Lastly, we present GenoME, a free, open-source educational app suitable for the lay public to allow exploration of personal genomes. Our findings demonstrate that citizen science-based approaches like PGP-UK have an important role to play in the public awareness, acceptance and implementation of genomics and personalized medicine.

genomics↗