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

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Merid, SK and Novoloaca, A and Sharp, GC and Kupers, LK and Kho, AT and Roy, R and Gao, L and Annesi-Maesano, I and Jain, P and Plusquin, M and Kogevinas, M and Allard, C and Vehmeijer, FO and Kazmi, N and Salas, LA and Rezwan, FI and Zhang, H and Sebert, S and Czamara, D and Rifas-Shiman, SL and Melton, PE and Lawlor, DA and Pershagen, G and Breton, CV and Huen, K and Baiz, N and Gagliardi, L and Nawrot, TS and Corpeleijn, E and Perron, P and Duijts, L and Nohr, EA and Bustamante, M and Ewart, SL and Karmaus, W and Zhao, S and Page, CM and Herceg, Z and Jarvelin, M-R and Lahti, J and Baccarelli, AA and Anderson, D and Kachroo, P and Relton, CL and Bergstrom, A and Eskenazi, B and Soomro, MH and Vineis, P and Snieder, H and Bouchard, L and Jaddoe, VW and Sorensen, TIA and Vrijheid, M and Arshad, SH and Holloway, JW and Haberg, SE and Magnus, P and Dwyer, T and Binder, EB and Demeo, DL and Vonk, JM and Newnham, J and Tantisira, KG and Kull, I and Wiemels, JL and Heude, B and Sunyer, J and Nystad, W and Munthe-Kaas, MC and Raikkonen, K and Oken, E and Huang, R-C and Weiss, ST and Anto, JM and Bousquet, J and Kumar, A and Soderhall, C and Almqvist, C and Cardenas, A and Gruzieva, O and Xu, C-J and Reese, SE and Kere, J and Brodin, P and Solomon, O and Wielscher, M and Holland, N and Ghantous, A and Hivert, M-F and Felix, JF and Koppelman, GH and London, SJ and Melen, E, Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age, Genome Medicine, 12, (1) pp. 1-17. ISSN 1756-994X (2020) [Refereed Article]


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Copyright 2020 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

DOI: doi:10.1186/s13073-020-0716-9

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.

Item Details

Item Type:Refereed Article
Keywords:development, epigenetics, gestational age, preterm birth, transcriptomics
Research Division:Biological Sciences
Research Group:Genetics
Research Field:Epigenetics (incl. genome methylation and epigenomics)
Objective Division:Health
Objective Group:Specific population health (excl. Indigenous health)
Objective Field:Neonatal and child health
UTAS Author:Melton, PE (Dr Phillip Melton)
ID Code:141834
Year Published:2020
Web of Science® Times Cited:5
Deposited By:Menzies Institute for Medical Research
Deposited On:2020-11-25
Last Modified:2020-12-10
Downloads:3 View Download Statistics

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