Maternal Smoking during Pregnancy and DNA-Methylation in Children at Age 5.5 Years: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study

PLoS One. 2016 May 12;11(5):e0155554. doi: 10.1371/journal.pone.0155554. eCollection 2016.

Abstract

Mounting evidence links prenatal exposure to maternal tobacco smoking with disruption of DNA methylation (DNAm) profile in the blood of infants. However, data on the postnatal stability of such DNAm signatures in childhood, as assessed by Epigenome Wide Association Studies (EWAS), are scarce. Objectives of this study were to investigate DNAm signatures associated with in utero tobacco smoke exposure beyond the 12th week of gestation in whole blood of children at age 5.5 years, to replicate previous findings in young European and American children and to assess their biological role by exploring databases and enrichment analysis. DNA methylation was measured in blood of 366 children of the multicentre European Childhood Obesity Project Study using the Illumina Infinium HM450 Beadchip (HM450K). An EWAS was conducted using linear regression of methylation values at each CpG site against in utero smoke exposure, adjusted for study characteristics, biological and technical effects. Methylation levels at five HM450K probes in MYO1G (cg12803068, cg22132788, cg19089201), CNTNAP2 (cg25949550), and FRMD4A (cg11813497) showed differential methylation that reached epigenome-wide significance according to the false-discovery-rate (FDR) criteria (q-value<0.05). Whereas cg25949550 showed decreased methylation (-2% DNAm ß-value), increased methylation was observed for the other probes (9%: cg12803068; 5%: cg22132788; 4%: cg19089201 and 4%: cg11813497) in exposed relative to non-exposed subjects. This study thus replicates previous findings in children ages 3 to 5, 7 and 17 and confirms the postnatal stability of MYO1G, CNTNAP2 and FRMD4A differential methylation. The role of this differential methylation in mediating childhood phenotypes, previously associated with maternal smoking, requires further investigation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Epigenesis, Genetic*
  • Europe
  • Female
  • Gene Regulatory Networks
  • Genome-Wide Association Study*
  • Humans
  • Male
  • Obesity / genetics*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / genetics*
  • Smoking / genetics*

Grants and funding

The studies and research reported herein were partially supported by the Commission of the European Community, specific RTD Programme “Quality of Life and Management of Living Resources,” within the 5th Framework Programme (research grant nos. QLRT-2001-00389 and QLK1-CT-2002-30582); the 6th Framework Programme (contract no. 007036); the European Union’s Seventh Framework Programme (FP7/2007-2013), project EarlyNutrition under grant agreement no. 289346 and the European Research Council Advanced Grant ERC-2012-AdG – no.322605 META-GROWTH. This manuscript does not necessarily reflect the views of the Commission and in no way anticipates the future policy in this area. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.