Longitudinal dynamics of epigenetics in early life: Uncovering genetic and environmental determinants from infancy to adolescence

DNA Methylation (DNAm) is an epigenetic modification involving the addition of a methyl group to DNA without altering the genetic sequence. DNAm can regulate gene expression and thereby influence phenotypes, including disease susceptibility. Genome-wide DNAm patterns are dynamic, changing throughout life in response to both endogenous factors (such as developmental processes and genetics) and exogenous factors (such as environmental exposures and disease). Early-life epigenetic changes may shape developmental trajectories and contribute to later disease risk. However, most epigenetic research to date has focused on adult cohorts and cross-sectional data, leaving major gaps in our understanding of how DNAm patterns develop in childhood and evolve over time. Here, we investigate the dynamics of DNAm across childhood and adolescence, focusing on two epigenetic biomarkers: (1) Epigenetic Age (EA) and (2) Methylation Quantitative Trait Loci (mQTLs). Epigenetic Age (EA) estimates an individual’s biological age based on ageassociated DNAm patterns. While EA has been widely studied in adults and shown to predict health and lifespan, its applicability in paediatric populations remains unclear. The increasing availability of longitudinal cohorts offers new opportunities to study EA trajectories, yet a lack of methodological consensus limits reproducibility. In this thesis, we first conducted simulation studies to identify appropriate approaches for modelling longitudinal EA. We then applied these methods to examine bidirectional associations between internalising Symptoms (IS) and EA from early childhood to early adulthood in two large, socioeconomically and ethnically distinct cohorts. Our results indicate that persistently high or increasing IS during childhood are associated with accelerated EA across childhood and adolescence. No evidence was found for the reverse effect - that is, accelerated EA did not predict later IS. These findings suggest that early mental health problems may shape biological ageing trajectories across development. Methylation Quantitative Trait Loci (mQTLs) are genetic variants that influence DNAm at specific sites. To date, no longitudinal studies have examined mQTL effects in early childhood, particularly in non-European populations. We analysed mQTL dynamics in a paediatric South African cohort, revealing diverse trajectories ranging from stable to increasing or attenuating effects across early childhood. Replication in independent cohorts supported the robustness of these findings and highlighted both age-related and ancestry-specific effects. These results indicate that early childhood represents a critical window during which genetic influences may disproportionately shape DNAm and, consequently, phenotypic development. Together, these studies provide novel insights into the dynamics of DNAm across childhood and adolescence and underscore the importance of longitudinal and diverse cohort designs to accurately capture epigenetic changes over time.

Funder

Research Ireland
European Commission

Publisher

University of Galway

Rights

CC BY-NC-ND

cbn

Collections

University of Galway Theses (PhD Theses)