title: Intra-individual changes in DNA methylation not mediated by cell-type composition are correlated with aging during childhood.
abstract: Several studies have reported age-associated changes in DNA methylation in the first few years of life and in adult populations, but the extent of such changes during childhood is less well studied. The goals of this study were to investigate to what degree intra-individual changes in DNA methylation are associated with aging during childhood and dissect the methylation changes directly associated with aging from the effect mediated through variation in cell-type composition (CTC).
  
  
  
  We performed reduced representation bisulfite sequencing (RRBS) in peripheral whole-blood samples collected at 2, 10, and 16 years of age. We identified age-associated longitudinal changes in DNA methylation at 346 CpGs in 178 genes. Analyses separating the effect mediated by CTC variability across age identified 26 CpGs located in 12 genes that associated directly with age. Hence, the CTC changes across age appear to act as a mediator of the observed DNA methylation associated with age. The results were replicated using EpiTYPER in a second sample set selected from the same cohort. Gene ontology analyses revealed enrichment of transcriptional regulation and developmental processes. Further, comparisons of the mean DNA methylation differences between the time points reveal greater differences between 2 to 10 years and 10 to 16 years, suggesting that the identified age-associated DNA methylation patterns manifests in early childhood.
  
  
  
  This study reveals insights into the epigenetic dynamics associated with aging early in life. Such information could ultimately provide clues and point towards molecular pathways that are susceptible to aging-related disease-associated epigenetic dysregulation.
authors: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors: Kristina
authors: 0000-0002-9851-1890
authors: K
authors: Gervin
authors: Department of Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.|Cancer Registry of Norway, Institute of population based Cancer Research, Oslo, Norway.
authors: Bettina Kulle
authors: BK
authors: Andreassen
authors: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors: Hanne Sagsveen
authors: HS
authors: Hjorthaug
authors: Department of Pediatrics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors: Karin C Lødrup
authors: KCL
authors: Carlsen
authors: Department of Pediatrics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors: Kai-Håkon
authors: KH
authors: Carlsen
authors: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors: Dag Erik
authors: DE
authors: Undlien
authors: Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.|School of Pharmacy, University of Oslo, Oslo, Norway.
authors: Robert
authors: R
authors: Lyle
authors: Department of Pediatrics, Section of Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
authors: Monica Cheng
authors: MC
authors: Munthe-Kaas
mesh_terms: D000293:Adolescent; D000375:Aging / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D063990:Gene Ontology; D006801:Humans; D008137:Longitudinal Studies; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods*
keywords: Aging; Cell-type composition; Childhood; DNA methylation; Longitudinal