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

Simon Kebede Merid, Alexei Novoloaca, Gemma C. Sharp, Leanne K. Kupers, Alvin T. Kho, Ritu Roy, Lu Gao, Isabella Annesi-Maesano, Pooja Jain, Michelle Plusquin, Manolis Kogevinas, Catherine Allard, Florianne O. Vehmeijer, Nabila Kazmi, Lucas A. Salas, Faisal I. Rezwan, Hongmei Zhang, Sylvain Sebert, Darina Czamara, Sheryl L. Rifas-ShimanPhillip E. Melton, Debbie A. Lawlor, Goran Pershagen, Carrie V. Breton, Karen Huen, Nour Baiz, Luigi Gagliardi, Tim S. Nawrot, Eva Corpeleijn, Patrice Perron, Liesbeth Duijts, Ellen Aagaard Nohr, Mariona Bustamante, Susan L. Ewart, Wilfried Karmaus, Shanshan Zhao, Christian M. Page, Zdenko Herceg, Marjo-Riitta Jarvelin, Jari Lahti, Andrea A. Baccarelli, Denise Anderson, Priyadarshini Kachroo, Caroline L. Relton, Anna Bergstrom, Brenda Eskenazi, Munawar Hussain Soomro, Paolo Vineis, Harold Snieder, Luigi Bouchard, Vincent W. Jaddoe, Thorkild I. A. Sorensen, Martine Vrijheid, S. Hasan Arshad, John W. Holloway, Siri E. Haberg, Per Magnus, Terence Dwyer, Elisabeth B. Binder, Dawn L. DeMeo, Judith M. Vonk, John Newnham, Kelan G. Tantisira, Inger Kull, Joseph L. Wiemels, Barbara Heude, Jordi Sunyer, Wenche Nystad, Monica C. Munthe-Kaas, Katri Raikkonen, Emily Oken, Rae-Chi Huang, Scott T. Weiss, Josep Maria Anto, Jean Bousquet, Ashish Kumar, Cilla Soderhall, Catarina Almqvist, Andres Cardenas, Olena Gruzieva, Cheng-Jian Xu, Sarah E. Reese, Juha Kere, Petter Brodin, Olivia Solomon, Matthias Wielscher, Nina Holland, Akram Ghantous, Marie-France Hivert, Janine F. Felix, Gerard H. Koppelman, Stephanie J. London, Erik Melen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Article number25
Pages (from-to)25
Number of pages17
JournalGenome medicine
Issue number1
Publication statusPublished - 2-Mar-2020


  • Development
  • Epigenetics
  • Gestational age
  • Preterm birth
  • Transcriptomics
  • RISK


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  • Additional file 1 of Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

    Perron, P. (Contributor), Baiz, N. (Contributor), Zhang, H. (Contributor), Magnus, P. (Contributor), Czamara, D. (Contributor), Jain, P. (Contributor), Huen, K. (Contributor), Snieder, H. (Contributor), Kachroo, P. (Contributor), Annesi-Maesano, I. (Contributor), Corpeleijn, E. (Contributor), Rifas-Shiman, S. L. (Contributor), Dwyer, T. (Contributor), Brodin, P. (Contributor), Holloway, J. W. (Contributor), Vonk, J. (Contributor), Kumar, A. (Contributor), Vrijheid, M. (Contributor), Sunyer, J. (Contributor), Herceg, Z. (Contributor), Binder, E. B. (Contributor), Ewart, S. L. (Contributor), Kull, I. (Contributor), Jarvelin, M. (Contributor), Antó, J. M. (Contributor), Bergström, A. (Contributor), Weiss, S. T. (Contributor), Solomon, O. (Contributor), Kho, A. T. (Contributor), Relton, C. L. (Contributor), Nawrot, T. S. (Contributor), Gao, L. (Contributor), Xu, C. (Contributor), Vehmeijer, F. O. (Contributor), Karmaus, W. (Contributor), Roy, R. (Contributor), Wiemels, J. L. (Contributor), Anderson, D. (Contributor), Wielscher, M. (Contributor), Nohr, E. A. (Contributor), Tantisira, K. G. (Contributor), Ghantous, A. (Contributor), London, S. J. (Contributor), Hivert, M. (Contributor), Sebert, S. (Contributor), Melton, P. E. (Contributor), Nystad, W. (Contributor), Bustamante, M. (Contributor), Bouchard, L. (Contributor), Holland, N. (Contributor), Reese, S. E. (Contributor), Page, C. M. (Contributor), Novoloaca, A. (Contributor), Lahti, J. (Contributor), Lawlor, D. A. (Contributor), Allard, C. (Contributor), Bousquet, J. (Contributor), Eskenazi, B. (Contributor), Kogevinas, M. (Contributor), Kazmi, N. (Contributor), Håberg, S. E. (Contributor), Raïkkönen, K. (Contributor), Oken, E. (Contributor), Munthe-Kaas, M. C. (Contributor), Sørensen, T. I. A. (Contributor), Sharp, G. C. (Contributor), Jaddoe, V. W. (Contributor), Arshad, S. H. (Contributor), Huang, R. (Contributor), Merid, S. K. (Contributor), Salas, L. A. (Contributor), Vineis, P. (Contributor), Duijts, L. (Contributor), Almqvist, C. (Contributor), Plusquin, M. (Contributor), Felix, J. F. (Contributor), Demeo, D. L. (Contributor), Heude, B. (Contributor), Breton, C. V. (Contributor), Pershagen, G. (Contributor), Baccarelli, A. A. (Contributor), Koppelman, G. (Contributor), Cardenas, A. (Contributor), Kere, J. (Contributor), Melén, E. (Contributor), Söderhäll, C. (Contributor), Gagliardi, L. (Contributor), Zhao, S. (Contributor), Soomro, M. H. (Contributor), Newnham, J. (Contributor), Rezwan, F. I. (Contributor), Gruzieva, O. (Contributor) & Küpers, L. K. (Contributor), University of Groningen, 2-Mar-2020


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