Genome Medicine (Mar 2020)
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. Küpers,
- 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-Shiman,
- Phillip E. Melton,
- Debbie A. Lawlor,
- Göran 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 Bergström,
- Brenda Eskenazi,
- Munawar Hussain Soomro,
- Paolo Vineis,
- Harold Snieder,
- Luigi Bouchard,
- Vincent W. Jaddoe,
- Thorkild I. A. Sørensen,
- Martine Vrijheid,
- S. Hasan Arshad,
- John W. Holloway,
- Siri E. Håberg,
- 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 Räikkönen,
- Emily Oken,
- Rae-Chi Huang,
- Scott T. Weiss,
- Josep Maria Antó,
- Jean Bousquet,
- Ashish Kumar,
- Cilla Söderhäll,
- 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 Melén
Affiliations
- Simon Kebede Merid
- Institute of Environmental Medicine, Karolinska Institutet
- Alexei Novoloaca
- Epigenetics Group, International Agency for Research on Cancer
- Gemma C. Sharp
- MRC Integrative Epidemiology Unit, University of Bristol
- Leanne K. Küpers
- Population Health Sciences, Bristol Medical School, University of Bristol
- Alvin T. Kho
- Computational Health Informatics Program, Boston Children’s Hospital and Harvard Medical School
- Ritu Roy
- Computational Biology And Informatics, University of California, San Francisco
- Lu Gao
- Department of Preventive Medicine, University of Southern California
- Isabella Annesi-Maesano
- Sorbonne Université and INSERM, Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Pierre Louis Institute of Epidemiology and Public Health (IPLESP UMRS 1136), Saint-Antoine Medical School
- Pooja Jain
- NIHR-Health Protection Research Unit, Respiratory Infections and Immunity, Imperial College London
- Michelle Plusquin
- NIHR-Health Protection Research Unit, Respiratory Infections and Immunity, Imperial College London
- Manolis Kogevinas
- ISGlobal, Barcelona Institute for Global Health
- Catherine Allard
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS)
- Florianne O. Vehmeijer
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Nabila Kazmi
- MRC Integrative Epidemiology Unit, University of Bristol
- Lucas A. Salas
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College
- Faisal I. Rezwan
- School of Water, Energy and Environment, Cranfield University
- Hongmei Zhang
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis
- Sylvain Sebert
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu
- Darina Czamara
- Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry
- Sheryl L. Rifas-Shiman
- Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute
- Phillip E. Melton
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University
- Debbie A. Lawlor
- MRC Integrative Epidemiology Unit, University of Bristol
- Göran Pershagen
- Institute of Environmental Medicine, Karolinska Institutet
- Carrie V. Breton
- Department of Preventive Medicine, University of Southern California
- Karen Huen
- Children’s Environmental Health Laboratory, University of California, Berkeley
- Nour Baiz
- Sorbonne Université and INSERM, Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Pierre Louis Institute of Epidemiology and Public Health (IPLESP UMRS 1136), Saint-Antoine Medical School
- Luigi Gagliardi
- Division of Neonatology and Pediatrics, Ospedale Versilia, Viareggio, AUSL Toscana Nord Ovest
- Tim S. Nawrot
- NIHR-Health Protection Research Unit, Respiratory Infections and Immunity, Imperial College London
- Eva Corpeleijn
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Patrice Perron
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS)
- Liesbeth Duijts
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Ellen Aagaard Nohr
- Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark
- Mariona Bustamante
- ISGlobal, Barcelona Institute for Global Health
- Susan L. Ewart
- College of Veterinary Medicine, Michigan State University
- Wilfried Karmaus
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis
- Shanshan Zhao
- Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health
- Christian M. Page
- Norwegian Institute of Public Health
- Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer
- Marjo-Riitta Jarvelin
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu
- Jari Lahti
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki
- Andrea A. Baccarelli
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center
- Denise Anderson
- Telethon Kids Institute, University of Western Australia
- Priyadarshini Kachroo
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
- Caroline L. Relton
- MRC Integrative Epidemiology Unit, University of Bristol
- Anna Bergström
- Institute of Environmental Medicine, Karolinska Institutet
- Brenda Eskenazi
- Center for Environmental Research and Children’s Health (CERCH), University of California, Berkeley
- Munawar Hussain Soomro
- Sorbonne Université and INSERM, Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Pierre Louis Institute of Epidemiology and Public Health (IPLESP UMRS 1136), Saint-Antoine Medical School
- Paolo Vineis
- MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London
- Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- Luigi Bouchard
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS)
- Vincent W. Jaddoe
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Thorkild I. A. Sørensen
- MRC Integrative Epidemiology Unit, University of Bristol
- Martine Vrijheid
- ISGlobal, Barcelona Institute for Global Health
- S. Hasan Arshad
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton
- John W. Holloway
- Human Development & Health, Faculty of Medicine, University of Southampton
- Siri E. Håberg
- Norwegian Institute of Public Health
- Per Magnus
- Norwegian Institute of Public Health
- Terence Dwyer
- Nuffield Department of Women’s and Reproductive Health, University of Oxford
- Elisabeth B. Binder
- Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry
- Dawn L. DeMeo
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
- Judith M. Vonk
- Department of Epidemiology, University of Groningen, University Medical Center Groningen
- John Newnham
- Faculty of Health and Medical Sciences, UWA Medical School, University of Western Australia
- Kelan G. Tantisira
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
- Inger Kull
- Department of Clinical Sciences and Education, Södersjukhuset, Karolinska Institutet
- Joseph L. Wiemels
- Center for Genetic Epidemiology, University of Southern California
- Barbara Heude
- INSERM, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Research Team on Early life Origins of Health (EarOH), Paris Descartes University
- Jordi Sunyer
- ISGlobal, Barcelona Institute for Global Health
- Wenche Nystad
- Norwegian Institute of Public Health
- Monica C. Munthe-Kaas
- Norwegian Institute of Public Health
- Katri Räikkönen
- Norwegian Institute of Public Health
- Emily Oken
- Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute
- Rae-Chi Huang
- Telethon Kids Institute, University of Western Australia
- Scott T. Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
- Josep Maria Antó
- ISGlobal, Barcelona Institute for Global Health
- Jean Bousquet
- University Hospital
- Ashish Kumar
- Institute of Environmental Medicine, Karolinska Institutet
- Cilla Söderhäll
- Department of Women’s and Children’s Health, Karolinska Institutet
- Catarina Almqvist
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet
- Andres Cardenas
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley
- Olena Gruzieva
- Institute of Environmental Medicine, Karolinska Institutet
- Cheng-Jian Xu
- University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, GRIAC Research Institute Groningen
- Sarah E. Reese
- Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health
- Juha Kere
- Department of Biosciences and Nutrition, Karolinska Institutet
- Petter Brodin
- Department of Women’s and Children’s Health, Karolinska Institutet
- Olivia Solomon
- Children’s Environmental Health Laboratory, University of California, Berkeley
- Matthias Wielscher
- Department of Epidemiology and Biostatistics, MRC–PHE Centre for Environment & Health, School of Public Health, Imperial College London
- Nina Holland
- Children’s Environmental Health Laboratory, University of California, Berkeley
- Akram Ghantous
- Epigenetics Group, International Agency for Research on Cancer
- Marie-France Hivert
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS)
- Janine F. Felix
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
- Gerard H. Koppelman
- University of Groningen, University Medical Center Groningen, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children’s Hospital, GRIAC Research Institute Groningen
- Stephanie J. London
- Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health
- Erik Melén
- Institute of Environmental Medicine, Karolinska Institutet
- DOI
- https://doi.org/10.1186/s13073-020-0716-9
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 17
Abstract
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.
Keywords
