Biology subjects

Ploubidis, G.

Publications and source records attributed to Ploubidis, G..

2 recordsLinked to original sources

bioRxiv2023

Genetic impacts on DNA methylation help elucidate regulatory genomic processes

Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk. We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2,358 blood samples from three UK cohorts, with replication. Methylation levels at 34.2% of CpGs were affected by SNPs, and 98% of effects were cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both meQTL SNPs and CpGs with meQTLs were overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identified 1,520 co-localisations across 1,325 unique CpGs and 34 phenotypes, including in disease-relevant genes, such ICOSLG (inflammatory bowel disease), and USP1 and DOCK7 (total cholesterol levels). Enrichment analysis of meQTLs and integration with expression QTLs gave insights into mechanisms underlying cis-meQTLs, for example through disruption of transcription factor binding sites for CTCF and SMC3, and trans-meQTLs, for example through regulating the expression of ACD and SENP7 which can modulate DNA methylation at distal sites. Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. A results database and viewer are available online.

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↗