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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. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age. Genome Med 2020; 12:25. [PMID: 32114984 PMCID: PMC7050134 DOI: 10.1186/s13073-020-0716-9] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 01/30/2020] [Indexed: 12/17/2022] Open
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.
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Affiliation(s)
- Simon Kebede Merid
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Sciences and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
| | - Alexei Novoloaca
- Epigenetics Group, International Agency for Research on Cancer, Lyon, France
| | - Gemma C Sharp
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Leanne K Küpers
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Alvin T Kho
- Computational Health Informatics Program, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA
| | - Ritu Roy
- Computational Biology And Informatics, University of California, San Francisco, San Francisco, CA, USA
- HDF Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
| | - Lu Gao
- Department of Preventive Medicine, University of Southern California, Los Angeles, USA
| | - 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, Paris, France
| | - Pooja Jain
- NIHR-Health Protection Research Unit, Respiratory Infections and Immunity, Imperial College London, London, UK
- Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK
| | - Michelle Plusquin
- NIHR-Health Protection Research Unit, Respiratory Infections and Immunity, Imperial College London, London, UK
- Centre for Environmental Sciences, Hasselt University, Hasselt, Belgium
| | - Manolis Kogevinas
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Catherine Allard
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada
| | - Florianne O Vehmeijer
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Nabila Kazmi
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Lucas A Salas
- Department of Epidemiology, Geisel School of Medicine, Dartmouth College, Lebanon, USA
| | - Faisal I Rezwan
- School of Water, Energy and Environment, Cranfield University, Cranfield, Bedfordshire, MK43 0AL, UK
| | - Hongmei Zhang
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, USA
| | - Sylvain Sebert
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Department of Genomic of Complex diseases, School of Public Health, Imperial College London, London, UK
| | - Darina Czamara
- Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany
| | - 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, Boston, MA, USA
| | - Phillip E Melton
- School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, Australia
- Curtin/UWA Centre for Genetic Origins of Health and Disease, School of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Australia
| | - Debbie A Lawlor
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Bristol NIHR Biomedical Research Centre, Bristol, UK
| | - Göran Pershagen
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Centre for Occupational and Environmental Medicine, Stockholm, Stockholm Region, Sweden
| | - Carrie V Breton
- Department of Preventive Medicine, University of Southern California, Los Angeles, USA
| | - Karen Huen
- Children's Environmental Health Laboratory, University of California, Berkeley, Berkeley, CA, USA
| | - 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, Paris, France
| | - Luigi Gagliardi
- Division of Neonatology and Pediatrics, Ospedale Versilia, Viareggio, AUSL Toscana Nord Ovest, Pisa, Italy
| | - Tim S Nawrot
- NIHR-Health Protection Research Unit, Respiratory Infections and Immunity, Imperial College London, London, UK
- Department of Public Health & Primary Care, Leuven University, Leuven, Belgium
| | - Eva Corpeleijn
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Patrice Perron
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada
- Department of Medicine, Université de Sherbrooke, Sherbrooke, Canada
| | - Liesbeth Duijts
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ellen Aagaard Nohr
- Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Mariona Bustamante
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - Susan L Ewart
- College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA
| | - Wilfried Karmaus
- Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, USA
| | - Shanshan Zhao
- Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, Durham, NC, USA
| | | | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer, Lyon, France
| | - Marjo-Riitta Jarvelin
- Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Biocenter Oulu, University of Oulu, Oulu, Finland
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK
- Unit of Primary Care, Oulu University Hospital, Oulu, Finland
| | - Jari Lahti
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Turku Institute for Advanced Studies, University of Turku, Turku, Finland
| | - Andrea A Baccarelli
- Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA
| | - Denise Anderson
- Telethon Kids Institute, University of Western Australia, Perth, Australia
| | - Priyadarshini Kachroo
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Caroline L Relton
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
- Bristol NIHR Biomedical Research Centre, Bristol, UK
| | - Anna Bergström
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Centre for Occupational and Environmental Medicine, Stockholm, Stockholm Region, Sweden
| | - Brenda Eskenazi
- Center for Environmental Research and Children's Health (CERCH), University of California, Berkeley, Berkeley, CA, USA
| | - 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, Paris, France
| | - Paolo Vineis
- MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
| | - Harold Snieder
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Luigi Bouchard
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada
- Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC, Canada
- Department of medical biology, CIUSSS-SLSJ, Saguenay, QC, Canada
| | - Vincent W Jaddoe
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Thorkild I A Sørensen
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Martine Vrijheid
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
| | - S Hasan Arshad
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- The David Hide Asthma and Allergy Research Centre, Newport, Isle of Wight, UK
| | - John W Holloway
- Human Development & Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Per Magnus
- Norwegian Institute of Public Health, Oslo, Norway
| | - Terence Dwyer
- Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
- Murdoch Children's Research Institute, Australia Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
| | - Elisabeth B Binder
- Department of Translational Research in Psychiatry, Max-Planck-Institute of Psychiatry, Munich, Germany
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, USA
| | - Dawn L DeMeo
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Judith M Vonk
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | - John Newnham
- Faculty of Health and Medical Sciences, UWA Medical School, University of Western Australia, Perth, Australia
| | - Kelan G Tantisira
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Inger Kull
- Department of Clinical Sciences and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
- Sachs' Children's Hospital, Södersjukhuset, 118 83, Stockholm, Sweden
| | - Joseph L Wiemels
- Center for Genetic Epidemiology, University of Southern California, Los Angeles, USA
| | - Barbara Heude
- INSERM, UMR1153 Epidemiology and Biostatistics Sorbonne Paris Cité Center (CRESS), Research Team on Early life Origins of Health (EarOH), Paris Descartes University, Paris, France
| | - Jordi Sunyer
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | | | - Monica C Munthe-Kaas
- Norwegian Institute of Public Health, Oslo, Norway
- Department of Pediatric Oncology and Hematology, Oslo University Hospital, Oslo, Norway
| | | | - Emily Oken
- Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Rae-Chi Huang
- Telethon Kids Institute, University of Western Australia, Perth, Australia
| | - Scott T Weiss
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Josep Maria Antó
- ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Jean Bousquet
- University Hospital, Montpellier, France
- Department of Dermatology, Charité, Berlin, Germany
| | - Ashish Kumar
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- University of Basel, Basel, Switzerland
- Swiss Tropical and Public Health Institute, Basel, Switzerland
| | - Cilla Söderhäll
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Catarina Almqvist
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Pediatric Allergy and Pulmonology Unit at Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
| | - Andres Cardenas
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
| | - Olena Gruzieva
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Centre for Occupational and Environmental Medicine, Stockholm, Stockholm Region, Sweden
| | - 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, Groningen, The Netherlands
| | - Sarah E Reese
- Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, Durham, NC, USA
| | - Juha Kere
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
- Folkhälsa Research Institute, Helsinki, and Stem Cells and Metabolism Research Program, University of Helsinki Finland, Helsinki, Finland
| | - Petter Brodin
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
- Department of Newborn Medicine, Karolinska University Hospital, Stockholm, Sweden
- Science for Life Laboratory, Stockholm, Sweden
| | - Olivia Solomon
- Children's Environmental Health Laboratory, University of California, Berkeley, Berkeley, CA, USA
| | - Matthias Wielscher
- Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment & Health, School of Public Health, Imperial College London, London, UK
| | - Nina Holland
- Children's Environmental Health Laboratory, University of California, Berkeley, Berkeley, CA, USA
| | - Akram Ghantous
- Epigenetics Group, International Agency for Research on Cancer, Lyon, France
| | - Marie-France Hivert
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada
- Division of Chronic Disease Research Across the Lifecourse (CoRAL), Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
- Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Janine F Felix
- The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - 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, Groningen, The Netherlands
| | - Stephanie J London
- Department of Health and Human Services, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, Durham, NC, USA
| | - Erik Melén
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Clinical Sciences and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
- Sachs' Children's Hospital, South General Hospital, Stockholm, Sweden.
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