Age-associated DNA methylation in pediatric populations

TLDR

DNA methylation is a dynamic epigenetic mark whose age‑associated changes are well documented in adults but remain largely unexplored in childhood, despite evidence of coordinated methylation patterns during early development. The study profiled 27,578 CpG sites in peripheral blood from 398 boys aged 3–17 and performed a meta‑analysis of 1,158 individuals, revealing that childhood methylation changes occur at a higher rate and are better described by a logarithmic age function than by a linear model. We identified 2,078 age‑associated CpG loci in children, replicated them in an independent cohort, found fewer X‑chromosome changes, nucleotide context preferences, and links to developmental and immune pathways, and showed that childhood methylation changes are faster and better modeled logarithmically, underscoring the need for age‑matched studies.

Abstract

DNA methylation (DNAm) plays diverse roles in human biology, but this dynamic epigenetic mark remains far from fully characterized. Although earlier studies uncovered loci that undergo age-associated DNAm changes in adults, little is known about such changes during childhood. Despite profound DNAm plasticity during embryogenesis, monozygotic twins show indistinguishable childhood methylation, suggesting that DNAm is highly coordinated throughout early development. Here we examine the methylation of 27,578 CpG dinucleotides in peripheral blood DNA from a cross-sectional study of 398 boys, aged 3–17 yr, and find significant age-associated changes in DNAm at 2078 loci. These findings correspond well with pyrosequencing data and replicate in a second pediatric population ( N = 78). Moreover, we report a deficit of age-related loci on the X chromosome, a preference for specific nucleotides immediately surrounding the interrogated CpG dinucleotide, and a primary association with developmental and immune ontological functions. Meta-analysis ( N = 1158) with two adult populations reveals that despite a significant overlap of age-associated loci, most methylation changes do not follow a lifelong linear pattern due to a threefold to fourfold higher rate of change in children compared with adults; consequently, the vast majority of changes are more accurately modeled as a function of logarithmic age. We therefore conclude that age-related DNAm changes in peripheral blood occur more rapidly during childhood and are imperfectly accounted for by statistical corrections that are linear in age, further suggesting that future DNAm studies should be matched closely for age.