Merid SK, Novoloaca A, Sharp GC, Küpers LK, Kho AT, Roy R, Gao L, Annesi-Maesano I, Jain P, Plusquin M, Kogevinas M, Allard C, Vehmeijer FO, Kazmi N, Salas LA, Rezwan FI, Zhang H, Sebert S, Czamara D, Rifas-Shiman SL, Melton PE, Lawlor DA, Pershagen G, Breton CV, Huen K, Baiz N, Gagliardi L, Nawrot TS, Corpeleijn E, Perron P, Duijts L, Nohr EA, Bustamante M, Ewart SL, Karmaus W, Zhao S, Page CM, Herceg Z, Jarvelin MR, Lahti J, Baccarelli AA, Anderson D, Kachroo P, Relton CL, Bergström A, Eskenazi B, Soomro MH, Vineis P, Snieder H, Bouchard L, Jaddoe VW, Sørensen TIA, Vrijheid M, Arshad SH, Holloway JW, Håberg SE, Magnus P, Dwyer T, Binder EB, DeMeo DL, Vonk JM, Newnham J, Tantisira KG, Kull I, Wiemels JL, Heude B, Sunyer J, Nystad W, Munthe-Kaas MC, Räikkönen K, Oken E, Huang RC, Weiss ST, Antó JM, Bousquet J, Kumar A, Söderhäll C, Almqvist C, Cardenas A, Gruzieva O, Xu CJ, Reese SE, Kere J, Brodin P, Solomon O, Wielscher M, Holland N, Ghantous A, Hivert MF, Felix JF, Koppelman GH, London SJ, Melén E
Genome Med 12 (1) 25 [2020-03-02; online 2020-03-02]
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. 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. 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. 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.