Timing matters in population epigenomics.

Abstract

DNA methylation (DNAm) is highly dynamic across the life course; yet, most studies examine it at a single time point and control for age in their analyses. Here we discuss how these practices risk obscuring epigenetic timing effects: age-dependent associations between exposures, DNAm, and health outcomes. We first synthesize growing evidence supporting the existence of epigenetic timing effects. We then outline how - when left unaccounted - these temporal dynamics can complicate the application and interpretation of common approaches in population epigenomics, including multi-cohort meta-analyses, epigenetic clocks, cell-type correction and methylation profile scores. Next, we provide practical recommendations and highlight priorities for moving from static to time-aware epigenetic research, emphasizing the need for repeated DNAm profiling and longitudinal designs. Finally, we discuss how awareness of epigenetic timing effects could ultimately enhance the translational potential of DNAm-based tools for early risk detection, stratification, diagnosis and monitoring.