Epigenetic timing effects on child developmental outcomes: a longitudinal meta-regression of findings from the Pregnancy And Childhood Epigenetics Consortium

Abstract

Background DNA methylation (DNAm) is a developmentally dynamic epigenetic process; yet, most epigenomewide association studies (EWAS) have examined DNAm at only one timepoint or without systematic comparisons between timepoints. Thus, it is unclear whether DNAm alterations during certain developmental periods are more informative than others for health outcomes, how persistent epigenetic signals are across time, and whether epige‑ netic timing efects difer by outcome. Methods We applied longitudinal meta-regression models to published meta-analyses from the PACE consortium that examined DNAm at two timepoints—prospectively at birth and cross-sectionally in childhood—in relation to the same child outcome (ADHD symptoms, general psychopathology, sleep duration, BMI, asthma). These mod‑ els allowed systematic comparisons of efect sizes and statistical signifcance between timepoints. Furthermore, we tested correlations between DNAm regression coefcients to assess the consistency of epigenetic signals across time and outcomes. Finally, we performed robustness checks, estimated between-study heterogeneity, and tested path‑ way enrichment. Results Our fndings reveal three new insights: (i) across outcomes, DNAm efect sizes are consistently larger in child‑ hood cross-sectional analyses compared to prospective analyses at birth; (ii) higher efect sizes do not necessarily translate into more signifcant fndings, as associations also become noisier in childhood for most outcomes (show‑ ing larger standard errors in cross-sectional vs prospective analyses); and (iii) DNAm signals are highly time-specifc, while also showing evidence of shared associations across health outcomes (ADHD symptoms, general psychopa‑ thology, and asthma). Notably, these observations could not be explained by sample size diferences and only partly to diferential study-heterogeneity. DNAm sites changing associations were enriched for neural pathways. Conclusions Our results highlight developmentally-specifc associations between DNAm and child health out‑ comes, when assessing DNAm at birth vs childhood. This implies that EWAS results from one timepoint are unlikely to generalize to another. Longitudinal studies with repeated epigenetic assessments are direly needed to shed light on the dynamic relationship between DNAm, development and health, as well as to enable the creation of more reliable and generalizable epigenetic biomarkers. More broadly, this study underscores the importance of considering the time-varying nature of DNAm in epigenetic research and supports the potential existence of epigenetic “timing efects” on child health.