DNA Methylation at Birth Showing Age-Specific Association with Atopy in Children: A Prospective Longitudinal Study

Background: The relationship between neonatal DNA methylation (DNAm) and childhood atopy, particularly its temporal dynamics, remains inadequately characterized. Establishing this will provide insights into the epigenetic mechanisms underlying atopy development. Methods: Skin prick tests (SPT) for 11 common allergens were performed in the Isle of Wight third-generation birth cohort (IOWF2) at ages 1, 3, and 6 years. Atopy was defined as a positive response to one or more allergens on SPT. DNAm at birth at 294,265 CpGs from umbilical cords (n = 192) or Guthrie cards (n = 107) was screened (through R package ttscreening) for potential association with atopy. Pathway enrichment analysis of screened CpGs was performed using the missMethyl package in R. Associations between CpGs that passed screening and atopy status were assessed via logistic regressions with repeated measures, adjusting for age, sex, and birth weight. Age-specific associations were examined via DNAm × age interactions. CpGs showing age-specific association were further tested in the parental cohort (IOWBC (F1); n = 717). Multiple testing was controlled using FDR-adjusted p-values at 0.05. Results: In total, 601 CpGs passed screening. Pathway enrichment analysis identified enrichment of the cell activation pathway (GO:0001775; FDR-adjusted p-value = 0.017). DNAm at 502 CpGs in F2 showed age-specific associations with atopy. Among these, 102 CpGs showed consistent directions in F1, and 14 were statistically significant (p-value < 0.05). Except for cg01519508 (FOXF1), DNAm-atopy associations weakened over time at the remaining 13 CpGs. Conclusions: At certain CpGs, DNAm at birth is associated with childhood atopy in an age-dependent manner, and for CpGs showing association at an earlier age, such associations weaken at later ages.