title: The emerging landscape of dynamic DNA methylation in early childhood.
abstract: DNA methylation has been found to associate with disease, aging and environmental exposure, but it is unknown how genome, environment and disease influence DNA methylation dynamics in childhood.
  
  
  
  By analysing 538 paired DNA blood samples from children at birth and at 4-5 years old and 726 paired samples from children at 4 and 8 years old from four European birth cohorts using the Illumina Infinium Human Methylation 450 k chip, we have identified 14,150 consistent age-differential methylation sites (a-DMSs) at epigenome-wide significance of p < 1.14 × 10-7. Genes with an increase in age-differential methylation were enriched in pathways related to 'development', and were more often located in bivalent transcription start site (TSS) regions, which can silence or activate expression of developmental genes. Genes with a decrease in age-differential methylation were involved in cell signalling, and enriched on H3K27ac, which can predict developmental state. Maternal smoking tended to decrease methylation levels at the identified da-DMSs. We also found 101 a-DMSs (0.71%) that were regulated by genetic variants using cis-differential Methylation Quantitative Trait Locus (cis-dMeQTL) mapping. Moreover, a-DMS-associated genes during early development were significantly more likely to be linked with disease.
  
  
  
  Our study provides new insights into the dynamic epigenetic landscape of the first 8 years of life.
authors.affiliation: Department of Pulmonology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. c.xu@umcg.nl.|Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. c.xu@umcg.nl.
authors.forename: Cheng-Jian
authors.initials: CJ
authors.lastname: Xu
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cilla
authors.initials: C
authors.lastname: Söderhäll
authors.affiliation: ISGlobal, Centre for Research in Environmental Epidemiology, Barcelona, Spain.|Centre for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona, Spain.|CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Bustamante
authors.affiliation: Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, UPMC Univ Paris 06, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France.
authors.forename: Nour
authors.initials: N
authors.lastname: Baïz
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gehring
authors.affiliation: Department of Pulmonology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.|Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Soesma A
authors.initials: SA
authors.lastname: Jankipersadsing
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: van der Vlies
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bianca
authors.initials: B
authors.lastname: van Rijkom
authors.affiliation: Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, UPMC Univ Paris 06, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France.|Department of Allergology-Centre de l'Asthme et des Allergies, Hôpital d'Enfants Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Just
authors.affiliation: Department of Clinical Science and Education, Stockholm South General Hospital, Karolinska Institutet, and Sachs' Children's Hospital, SE-118 83, Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Kull
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|Folkhälsan Institute of Genetics and Research Programs Unit, University of Helsinki, Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: ISGlobal, Centre for Research in Environmental Epidemiology, 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.
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Antó
authors.affiliation: University Hospital, Montpellier, France.|MACVIA-France, Contre les Maladies Chroniques pour un VIeillissement Actif en France, European Innovation Partnership on Active and Healthy Ageing Reference Site, Paris, France.|INSERM, VIMA: Ageing and chronic diseases. Epidemiological and public health approaches, U1168, Paris, France.|UVSQ, UMR-S 1168, Université Versailles St-Quentin-en-Yvelines, Versailles, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Bousquet
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Sorbonne Université, UPMC Univ Paris 06, INSERM, Pierre Louis Institute of Epidemiology and Public Health, Saint-Antoine Medical School, Paris, France.
authors.forename: Isabella
authors.initials: I
authors.lastname: Annesi-Maesano
authors.affiliation: ISGlobal, Centre for Research in Environmental Epidemiology, 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.
authors.forename: Jordi
authors.initials: J
authors.lastname: Sunyer
authors.affiliation: Department of Paediatric Pulmonology and Paediatric Allergy, Beatrix Children's Hospital, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Melén
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. y.li01@umcg.nl.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pulmonology, GRIAC Research Institute, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Paediatric Pulmonology and Paediatric Allergy, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, GRIAC Research Institute, Groningen, The Netherlands.
authors.forename: Gerard H
authors.initials: GH
authors.lastname: Koppelman
mesh_terms: D002648:Child; D002657:Child Development; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018811:Maternal Exposure / Q000009:adverse effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D040641:Quantitative Trait Loci; D012907:Smoking / Q000009:adverse effects
keywords: Aging; DNA methylation; Maternal smoking; Methylation quantitative trait loci