DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring

Leanne K Küpers, Xiaojing Xu, Soesma A Jankipersadsing, Ahmad Vaez, Sacha la Bastide-van Gemert, Salome Scholtens, Ilja M Nolte, Rebecca C Richmond, Caroline L Relton, Janine F Felix, Liesbeth Duijts, Joyce B van Meurs, Henning Tiemeier, Vincent W Jaddoe, Xiaoling Wang, Eva Corpeleijn, Harold Snieder

Research output: Contribution to journalArticle (Academic Journal)peer-review

97 Citations (Scopus)


BACKGROUND: We examined whether the effect of maternal smoking during pregnancy on birthweight of the offspring was mediated by smoking-induced changes to DNA methylation in cord blood.

METHODS: First, we used cord blood of 129 Dutch children exposed to maternal smoking vs 126 unexposed to maternal and paternal smoking (53% male) participating in the GECKO Drenthe birth cohort. DNA methylation was measured using the Illumina HumanMethylation450 Beadchip. We performed an epigenome-wide association study for the association between maternal smoking and methylation followed by a mediation analysis of the top signals [false-discovery rate (FDR) < 0.05]. We adjusted both analyses for maternal age, education, pre-pregnancy BMI, offspring's sex, gestational age and white blood cell composition. Secondly, in 175 exposed and 1248 unexposed newborns from two independent birth cohorts, we replicated and meta-analysed results of eight cytosine-phosphate-guanine (CpG) sites in the GFI1 gene, which showed the most robust mediation. Finally, we performed functional network and enrichment analysis.

RESULTS: We found 35 differentially methylated CpGs (FDR < 0.05) in newborns exposed vs unexposed to smoking, of which 23 survived Bonferroni correction (P < 1 × 10(-7)). These 23 CpGs mapped to eight genes: AHRR, GFI1, MYO1G, CYP1A1, NEUROG1, CNTNAP2, FRMD4A and LRP5. We observed partial confirmation as three of the eight CpGs in GFI1 replicated. These CpGs partly mediated the effect of maternal smoking on birthweight (Sobel P < 0.05) in meta-analysis of GECKO and the two replication cohorts. Differential methylation of these three GFI1 CpGs explained 12-19% of the 202 g lower birthweight in smoking mothers. Functional enrichment analysis pointed towards activation of cell-mediated immunity.

CONCLUSIONS: Maternal smoking during pregnancy was associated with cord blood methylation differences. We observed a potentially mediating role of methylation in the association between maternal smoking during pregnancy and birthweight of the offspring. Functional network analysis suggested a role in activating the immune system.

Original languageEnglish
Pages (from-to)1224-1237
Number of pages14
JournalInternational Journal of Epidemiology
Issue number4
Publication statusPublished - 10 Apr 2015

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