Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth

Alfano, Rossella; Zugna, Daniela; Barros, Henrique; Bustamante Pineda, Mariona; Chatzi, Leda; Ghantous, Akram; Herceg, Zdenko; Keski-Rahkonen, Pekka; Kok, Theo M. de; Nawrot, Tim S.; Relton, Caroline L.; Robinson, Oliver; Roumeliotaki, Theano; Scalbert, Augustin; Vrijheid, Martine; Vineis, Paolo; Richiardi, Lorenzo; Plusquin, Michelle

Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth

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dc.contributor.author Alfano, Rossella
dc.contributor.author Zugna, Daniela
dc.contributor.author Barros, Henrique
dc.contributor.author Bustamante Pineda, Mariona
dc.contributor.author Chatzi, Leda
dc.contributor.author Ghantous, Akram
dc.contributor.author Herceg, Zdenko
dc.contributor.author Keski-Rahkonen, Pekka
dc.contributor.author Kok, Theo M. de
dc.contributor.author Nawrot, Tim S.
dc.contributor.author Relton, Caroline L.
dc.contributor.author Robinson, Oliver
dc.contributor.author Roumeliotaki, Theano
dc.contributor.author Scalbert, Augustin
dc.contributor.author Vrijheid, Martine
dc.contributor.author Vineis, Paolo
dc.contributor.author Richiardi, Lorenzo
dc.contributor.author Plusquin, Michelle
dc.date.accessioned 2023-03-20T07:24:36Z
dc.date.available 2023-03-20T07:24:36Z
dc.date.issued 2023
dc.description.abstract Rapid 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.
dc.description.sponsorship This work is supported by the Bijzonder Onderzoeksfonds Hasselt University through a PhD fellowship [to RA], by the UKRI Future Leaders Fellowship [MR/S03532X/1, to OR], by the European FP7 Grant to “EXPOsOMICS” project [Grant ref 308610], and by the European Commission Horizon 2020 Grant to the “STOP Project” [Grant ref 774548]. ALSPAC was provided core support by the United Kingdom Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large-scale methylation data was funded by the United Kingdom Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the United Kingdom Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, and MC_UU_12013_8), the Wellcome Trust (WT088806), and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The ENVIRONAGE birth cohort is supported by the European Research Council [ERC-2012-StG.310898] and by funds of the Flemish Scientific Research council [FWO, G.073315N, G059219N]. This INMA study was funded by grants from Instituto de Salud Carlos III (Red INMA G03/176; CB06/02/0041; PI041436; PI081151 incl. FEDER funds), Generalitat de Catalunya-CIRIT 1999SGR 00241, Fundació La marató de TV3 (090430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: BRain dEvelopment and Air polluTion ultrafine particles in scHool childrEn). We acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S) and support from the Generalitat de Catalunya through the CERCA Program. The Piccolipiù cohort was initially supported by the Italian National Center for Disease Prevention and Control (CCM grants years 2010 and 2014) and by the Italian Ministry of Health (art 12 and 12 bis D.lgs 502/92). The Rhea study has been funded by various European grants since 2006 and by the Greek Ministry of Health. The GXXI cohort is funded by Programa Operacional de Saúde – Saúde XXI, Quadro Comunitário de Apoio III and Administração Regional de Saúde Norte (Regional Department of Ministry of Health).
dc.format.mimetype application/pdf
dc.identifier.citation Alfano 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/s12916-022-02685-7
dc.identifier.doi http://dx.doi.org/10.1186/s12916-022-02685-7
dc.identifier.issn 1741-7015
dc.identifier.uri http://hdl.handle.net/10230/56274
dc.language.iso eng
dc.publisher BioMed Central
dc.relation.ispartof BMC Medicine. 2023 Jan 11;21(1):17
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/308610
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/310898
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/774548
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/261357
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/268479
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2018-000806-S
dc.rights This 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.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Rapid weight growth
dc.subject.keyword Weight gain
dc.subject.keyword DNA methylation
dc.subject.keyword Gestational age acceleration
dc.subject.keyword Childhood overweight
dc.subject.keyword AURKC
dc.subject.keyword Gene expression
dc.title Cord blood epigenome-wide meta-analysis in six European-based child cohorts identifies signatures linked to rapid weight growth
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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