title: Prenatal exposure to maternal cigarette smoking and DNA methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age.
abstract: BACKGROUND
  Prenatal exposure to maternal cigarette smoking (prenatal smoke exposure) had been associated with altered DNA methylation (DNAm) at birth.
  
  
  OBJECTIVE
  We examined whether such alterations are present from birth through adolescence.
  
  
  METHODS
  We used the Infinium HumanMethylation450K BeadChip to search across 473,395 CpGs for differential DNAm associated with prenatal smoke exposure during adolescence in a discovery cohort (n = 132) and at birth, during childhood, and during adolescence in a replication cohort (n = 447).
  
  
  RESULTS
  In the discovery cohort, we found five CpGs in MYO1G (top-ranking CpG: cg12803068, p = 3.3 × 10-11) and CNTNAP2 (cg25949550, p = 4.0 × 10-9) to be differentially methylated between exposed and nonexposed individuals during adolescence. The CpGs in MYO1G and CNTNAP2 were associated, respectively, with higher and lower DNAm in exposed versus nonexposed adolescents. The same CpGs were differentially methylated at birth, during childhood, and during adolescence in the replication cohort. In both cohorts and at all developmental time points, the differential DNAm was in the same direction and of a similar magnitude, and was not altered appreciably by adjustment for current smoking by the participants or their parents. In addition, four of the five EWAS (epigenome-wide association study)-significant CpGs in the adolescent discovery cohort were also among the top sites of differential methylation in a previous birth cohort, and differential methylation of CpGs in CYP1A1, AHRR, and GFI1 observed in that study was also evident in our discovery cohort.
  
  
  CONCLUSIONS
  Our findings suggest that modifications of DNAm associated with prenatal maternal smoking may persist in exposed offspring for many years-at least until adolescence.
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ken W K
authors.initials: KW
authors.lastname: Lee
authors.forename: Rebecca
authors.initials: R
authors.lastname: Richmond
authors.forename: Pingzhao
authors.initials: P
authors.lastname: Hu
authors.forename: Leon
authors.initials: L
authors.lastname: French
authors.forename: Jean
authors.initials: J
authors.lastname: Shin
authors.forename: Celine
authors.initials: C
authors.lastname: Bourdon
authors.forename: Eva
authors.initials: E
authors.lastname: Reischl
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.forename: Sonja
authors.initials: S
authors.lastname: Zeilinger
authors.forename: Tom
authors.initials: T
authors.lastname: Gaunt
authors.forename: Wendy
authors.initials: W
authors.lastname: McArdle
authors.forename: Susan
authors.initials: S
authors.lastname: Ring
authors.forename: Geoff
authors.initials: G
authors.lastname: Woodward
authors.forename: Luigi
authors.initials: L
authors.lastname: Bouchard
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Caroline
authors.initials: C
authors.lastname: Relton
authors.forename: Tomas
authors.initials: T
authors.lastname: Paus
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Pausova
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D015331:Cohort Studies; D019175:DNA Methylation; D004739:England / Q000453:epidemiology; D044127:Epigenesis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011792:Quebec / Q000453:epidemiology; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology*