Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

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• dc.contributor.author Merid, Simon Kebede
• dc.contributor.author Kogevinas, Manolis
• dc.contributor.author Bustamante Pineda, Mariona
• dc.contributor.author Vrijheid, Martine
• dc.contributor.author Sunyer Deu, Jordi
• dc.contributor.author Antó i Boqué, Josep Maria
• dc.contributor.author Melén, Erik
• dc.date.accessioned 2020-06-05T06:28:27Z
• dc.date.available 2020-06-05T06:28:27Z
• dc.date.issued 2020
• dc.description.abstract Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
• dc.description.sponsorship This study was specifically funded by a grant from the European Research Council (TRIBAL, grant agreement 757919). For all studies, detailed information can be found in Additional file 2: Supplementary information. Open access funding provided by Uppsala University.
• dc.format.mimetype application/pdf
• dc.identifier.citation Merid SK, Novoloaca A, Sharp GC, Küpers LK, Kho AT, Roy R, et al. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age. Genome Med. 2020 Mar 2; 12(1):25. DOI: 10.1186/s13073-020-0716-9
• dc.identifier.doi http://dx.doi.org/10.1186/s13073-020-0716-9
• dc.identifier.issn 1756-994X
• dc.identifier.uri http://hdl.handle.net/10230/44911
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Medicine. 2020 Mar 2;12(1):25
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/757919
• dc.rights Copyright © The Author(s). 2020. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Development
• dc.subject.keyword Epigenetics
• dc.subject.keyword Gestational age
• dc.subject.keyword Preterm birth
• dc.subject.keyword Transcriptomics
• dc.title Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion