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- Title
DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring.
- Authors
Küpers, Leanne K.; Xiaojing Xu; Jankipersadsing, Soesma A.; Vaez, Ahmad; Gemert, Sacha la Bastide-van; Scholtens, Salome; Nolte, Ilja M.; Richmond, Rebecca C.; Relton, Caroline L.; Felix, Janine F.; Duijts, Liesbeth; van Meurs, Joyce B.; Tiemeier, Henning; Jaddoe, Vincent W.; Xiaoling Wang; Corpeleijn, Eva; Snieder, Harold; Xu, Xiaojing; la Bastide-van Gemert, Sacha; Wang, Xiaoling
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
HEALTH; SMOKING; PREGNANT women; WOMEN'S tobacco use; BIRTH weight; DNA methylation; CORD blood; CYTOSINE; COHORT analysis; GENES; LONGITUDINAL method; REGRESSION analysis; RESEARCH funding; TRANSCRIPTION factors; DNA-binding proteins; PRENATAL exposure delayed effects; SEQUENCE analysis; MATERNAL exposure
- Publication
International Journal of Epidemiology, 2015, Vol 44, Issue 4, p1224
- ISSN
0300-5771
- Publication type
journal article
- DOI
10.1093/ije/dyv048