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

作者：Alexander Neumann, Sara Sammallahti, Marta Cosín‐Tomás, Sarah E. Reese, Matthew Suderman, Silvia Alemany, Catarina Almqvist, Sandra Andrušaitytė, Syed Hasan Arshad, Marian J. Bakermans‐Kranenburg, Lawrence J. Beilin, Carrie V. Breton, Mariona Bustamante, Darina Czamara, Dana Dabelea, Celeste Eng, Brenda Eskenazi, Bernard F. Fuemmeler, Frank D. Gilliland, Regina Gražulevičienė, Siri E. Håberg, Gunda Herberth, Nina Holland, Amy Hough, Donglei Hu, Karen Huen, Anke Hüls, Marjo‐Riitta Järvelin, Jianping Jin, Jordi Júlvez, Berthold Koletzko, Gerard H. Koppelman, Inger Kull, Xueling Lu, Léa Maître, Dan Mason, Erik Melén, Simon Kebede Merid, Peter L. Molloy, Trevor A. Mori, Rosa H. Mulder, Christian M. Page, Rebecca C. Richmond, Stefan Röder, Jason P. Ross, Laura Schellhas, Sylvain Sebért, Dean Sheppard, Harold Snieder, Anne P. Starling, Dan J. Stein, Gwen Tindula, Marinus H. van IJzendoorn, Judith M. Vonk, Esther Walton, Jonathan Witonsky, Cheng‐Jian Xu, Ivana V. Yang, Paul Yousefi, Heather J. Zar, Ana Claudia Zenclussen, Hongmei Zhang, Henning Tiemeier, Stephanie J. London, Janine F. Felix, Charlotte A. M. Cecil · 发表于：Genome Medicine · 年份：2025 · DOI：10.1186/s13073-025-01451-7 · 被引用次数：15 · 研究领域：Epigenetics and DNA Methylation、Health, Environment, Cognitive Aging、Cancer-related gene regulation

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 ...