Epigenome-wide change and variation in DNA methylation in childhood: trajectories from birth to late adolescence.

Rosa H Mulder,Marian J Bakermans-Kranenburg,Janine F Felix,Caroline L Relton,Andrew J Simpkin,Vincent W V Jaddoe,Charlotte A M Cecil,Matthew Suderman,Bastiaan T Heijmans,Tom R Gaunt,Lotte C Houtepen,Esther Walton,Alexander Neumann,Jolien Rijlaarsdam,Henning Tiemeier,Marinus H Van Ijzendoorn

doi:10.1093/hmg/ddaa280

Abstract

DNA methylation (DNAm) is known to play a pivotal role in childhood health and development, but a comprehensive characterization of genome-wide DNAm trajectories across this age period is currently lacking. We have therefore performed a series of epigenome-wide association studies in 5019 blood samples collected at multiple time-points from birth to late adolescence from 2348 participants of two large independent cohorts. DNAm profiles of autosomal CpG sites (CpGs) were generated using the Illumina Infinium HumanMethylation450 BeadChip. Change over time was widespread, observed at over one-half (53%) of CpGs. In most cases, DNAm was decreasing (36% of CpGs). Inter-individual variation in linear trajectories was similarly widespread (27% of CpGs). Evidence for non-linear change and inter-individual variation in non-linear trajectories was somewhat less common (11 and 8% of CpGs, respectively). Very little inter-individual variation in change was explained by sex differences (0.4% of CpGs) even though sex-specific DNAm was observed at 5% of CpGs. DNAm trajectories were distributed non-randomly across the genome. For example, CpGs with decreasing DNAm were enriched in gene bodies and enhancers and were annotated to genes enriched in immune-developmental functions. In contrast, CpGs with increasing DNAm were enriched in promoter regions and annotated to genes enriched in neurodevelopmental functions. These findings depict a methylome undergoing widespread and often non-linear change throughout childhood. They support a developmental role for DNA methylation that extends beyond birth into late adolescence and has implications for understanding life-long health and disease. DNAm trajectories can be visualized at http://epidelta.mrcieu.ac.uk.

Highlights

DNA methylation (DNAm), an epigenetic process whereby DNA is modified by the addition of methyl groups, has gained increasing attention over the past few decades, due to its pivotal role in development
We further report the enrichment of Gene Ontology (GO) pathways for genes annotated to CpG sites in each trajectory (Supplementary Material, Tables S12–S14)
We looked up methylation quantitative trait loci in cis and in trans [45] and CpGs located on a single nucleotide polymorphism [46] to investigate possible relationships between genetic variation and DNAm trajectories and sex differences

Summary

Introduction

DNA methylation (DNAm), an epigenetic process whereby DNA is modified by the addition of methyl groups, has gained increasing attention over the past few decades, due to its pivotal role in development. Its role extends well beyond birth, e.g. by maintaining cell type identity and genome stability [6,7,8], responding to environmental exposures [9,10,11], and its involvement, among many other processes, in immune [12] and neural development [13]. Since it is influenced by both genetic and environmental factors [14,15], DNAm has emerged as a key mechanism of interest for understanding the gene-environmental interplay in normal ageing and disease development. Little is known about DNAm trajectories across early development, as existing studies in childhood DNAm typically have been limited by small sample sizes [21,23], short time-periods [22,28] or focused on specific CpGs in relation to maternal smoking [29], birthweight [30] or maternal BMI [31]

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Discussion

Conclusion