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

Abstract

DNA methylation; Epigenetics; Sleep

Epigenètica; Pediatria; Son

Epigenética; Pediatría; Sueño

Background DNA methylation (DNAm) is a developmentally dynamic epigenetic process; yet, most epigenome-wide 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 epigenetic timing effects differ 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 models allowed systematic comparisons of effect sizes and statistical significance between timepoints. Furthermore, we tested correlations between DNAm regression coefficients to assess the consistency of epigenetic signals across time and outcomes. Finally, we performed robustness checks, estimated between-study heterogeneity, and tested pathway enrichment. Results Our findings reveal three new insights: (i) across outcomes, DNAm effect sizes are consistently larger in childhood cross-sectional analyses compared to prospective analyses at birth; (ii) higher effect sizes do not necessarily translate into more significant findings, as associations also become noisier in childhood for most outcomes (showing larger standard errors in cross-sectional vs prospective analyses); and (iii) DNAm signals are highly time-specific, while also showing evidence of shared associations across health outcomes (ADHD symptoms, general psychopathology, and asthma). Notably, these observations could not be explained by sample size differences and only partly to differential study-heterogeneity. DNAm sites changing associations were enriched for neural pathways. Conclusions Our results highlight developmentally-specific associations between DNAm and child health outcomes, 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 effects” on child health.

The work of AN and CAMC was supported by the European Research Council (TEMPO; grant agreement No 101039672) and the European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529). The work of CAMC is further supported by the European Union’s Horizon 2020 Research and Innovation Programme (EarlyCause, grant agreement No 848158; HappyMums, grant agreement No 101057390). CAMC and JFF are supported by the European Union’s Horizon Europe Programme (STAGE project, grant agreement no.101137146). This research was conducted while CAMC was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. LST was supported by the CAPICE (Childhood and Adolescence Psychopathology: unravelling the complex etiology by a large Interdisciplinary Collaboration in Europe) project, the European Union’s Horizon 2020 research and innovation program, Marie Sklodowska Curie Actions – MSCA-ITN-2016 – Innovative Training Networks under grant agreement number 721567. SJL was supported in part by the Intramural Research Program of the NIH (NIEHS Z01 ES49019). SEH and CMP were partly supported by The Norwegian Research Council no 262700 and the Norwegian Cancer Society project no 244291. See additional file 3 for cohort-specific funding.