Biology subjects

Silver, M. J.

Publications and source records attributed to Silver, M. J..

4 recordsLinked to original sources

bioRxiv2025

DNA methylation marks associated with body composition in children from India and the Gambia - findings from the EMPHASIS study

BackgroundDifferences in body composition during childhood can influence long-term health, with notable links to cardiometabolic disorders in later life. While genetic associations with body composition traits are well-studied, less is known about the role of epigenetic mechanisms, particularly in low- and middle-income countries where the burden of cardiometabolic disease is high. We investigated links between DNA methylation and three compartments of body composition: fat mass, lean mass, and bone measures using data from children enrolled in the Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa (EMPHASIS) study. ResultsWe conducted an epigenome-wide association study (EWAS) of 11 body composition traits assessed through dual-energy X-ray absorptiometry in children from India (age = 5-7 years, n = 686) and The Gambia (age = 7-9 years, n = 289), with blood DNA methylation measured at approximately 800,000 CpGs sites on on the Illumina EPIC array. Cohort-specific analysis identified 15 unique differentially methylated CpGs (dmCpGs) associated with traits across all three compartments of body composition (p<3.6x10-8). Cross-cohort meta-analysis revealed 4 loci associated with lean mass and bone area. Notably, dmCpGs mapping to the SOCS3 gene, previously linked to height in Indian, African and European populations, were associated with lean mass and bone area in both the Indian cohort and combined meta-analyses. Region-level EWAS identified differentially methylated regions (DMRs), linked to lean mass and bone area mapping to SOCS3 and P4HB genes overlapping identified dmCpGs associated with the same phenotypes. Other DMRs mapped to genes including BPNT1, RNU5F-1, LTA, HIF1A, HIF1A-AS1, MTHFD1, and TRIM72 were associated with multiple traits. ConclusionWe report novel DNA methylation signatures associated with body composition traits in children from two low- and middle-income countries, highlighting a potential role for epigenetic mechanisms in shaping early-life body composition.

genomics↗

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

Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo

We analysed DNA methylation data from 30 datasets comprising 3,474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4,143 hypervariable CpGs ("hvCpGs") with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for associations with periconceptional environment, proximity to ERV1 and ERVK retrovirus elements and parent-of-origin-specific methylation. They also showed distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.

genomics↗

bioRxiv2019

Environmentally sensitive hotspots in the methylome of the early human embryo

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin specific methylation and germline DMRs, supporting a periconceptional environmental influence. Many SoC-sensitive CpGs overlapped enhancers or sites of active transcription in H1 ESCs and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental hotspots providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.

genomics↗