Alfano, RossellaZugna, DanielaBarros, HenriqueBustamante Pineda, MarionaChatzi, LedaGhantous, AkramHerceg, ZdenkoKeski-Rahkonen, PekkaKok, Theo M. deNawrot, Tim S.Relton, Caroline L.Robinson, OliverRoumeliotaki, TheanoScalbert, AugustinVrijheid, MartineVineis, PaoloRichiardi, LorenzoPlusquin, Michelle2023-03-202023-03-202023Alfano R, Zugna D, Barros H, Bustamante M, Chatzi L, Ghantous A, et al. Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth. BMC Med. 2023 Jan 11;21(1):17. DOI: 10.1186/s12916-022-02685-71741-7015http://hdl.handle.net/10230/56274Rapid postnatal growth may result from exposure in utero or early life to adverse conditions and has been associated with diseases later in life and, in particular, with childhood obesity. DNA methylation, interfacing early-life exposures and subsequent diseases, is a possible mechanism underlying early-life programming. Here, a meta-analysis of Illumina HumanMethylation 450K/EPIC-array associations of cord blood DNA methylation at single CpG sites and CpG genomic regions with rapid weight growth at 1 year of age (defined with reference to WHO growth charts) was conducted in six European-based child cohorts (ALSPAC, ENVIRONAGE, Generation XXI, INMA, Piccolipiù, and RHEA, N = 2003). The association of gestational age acceleration (calculated using the Bohlin epigenetic clock) with rapid weight growth was also explored via meta-analysis. Follow-up analyses of identified DNA methylation signals included prediction of rapid weight growth, mediation of the effect of conventional risk factors on rapid weight growth, integration with transcriptomics and metabolomics, association with overweight in childhood (between 4 and 8 years), and comparison with previous findings. Forty-seven CpGs were associated with rapid weight growth at suggestive p-value <1e−05 and, among them, three CpGs (cg14459032, cg25953130 annotated to ARID5B, and cg00049440 annotated to KLF9) passed the genome-wide significance level (p-value <1.25e−07). Sixteen differentially methylated regions (DMRs) were identified as associated with rapid weight growth at false discovery rate (FDR)-adjusted/Siddak p-values < 0.01. Gestational age acceleration was associated with decreasing risk of rapid weight growth (p-value = 9.75e−04). Identified DNA methylation signals slightly increased the prediction of rapid weight growth in addition to conventional risk factors. Among the identified signals, three CpGs partially mediated the effect of gestational age on rapid weight growth. Both CpGs (N=3) and DMRs (N=3) were associated with differential expression of transcripts (N=10 and 7, respectively), including long non-coding RNAs. An AURKC DMR was associated with childhood overweight. We observed enrichment of CpGs previously reported associated with birthweight. Our findings provide evidence of the association between cord blood DNA methylation and rapid weight growth and suggest links with prenatal exposures and association with childhood obesity providing opportunities for early prevention.application/pdfengThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1186/s12916-022-02685-7Rapid weight growthWeight gainDNA methylationGestational age accelerationChildhood overweightAURKCGene expressioninfo:eu-repo/semantics/openAccess