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

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Abstract

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 (US)
Pages (from-to)1224-1237
Number of pages14
JournalInternational Journal of Epidemiology
Volume44
Issue number4
DOIs
StatePublished - Aug 1 2015

Fingerprint

DNA Methylation
Smoking
Mothers
Pregnancy
Methylation
Fetal Blood
Parturition
Newborn Infant
Cytochrome P-450 CYP1A1
Cytosine
Maternal Age
Guanine
Cellular Immunity
Genes
Gestational Age
Meta-Analysis
Immune System
Leukocytes
Phosphates
Education

Keywords

  • ALSPAC
  • DOHaD
  • Epigenetic epidemiology
  • Epigenome-wide association study
  • Fetal programming
  • GECKO
  • Generation R

ASJC Scopus subject areas

  • Epidemiology

Cite this

Küpers, L. K., Xu, X., Jankipersadsing, S. A., Vaez, A., La Bastide-van Gemert, S., Scholtens, S., ... Snieder, H. (2015). DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. International Journal of Epidemiology, 44(4), 1224-1237. https://doi.org/10.1093/ije/dyv048

DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. / Küpers, Leanne K.; Xu, Xiaojing; Jankipersadsing, Soesma A.; Vaez, Ahmad; La Bastide-van Gemert, Sacha; 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.; Wang, Xiaoling; Corpeleijn, Eva; Snieder, Harold.

In: International Journal of Epidemiology, Vol. 44, No. 4, 01.08.2015, p. 1224-1237.

Research output: Contribution to journalArticle

Küpers, LK, Xu, X, Jankipersadsing, SA, Vaez, A, La Bastide-van Gemert, S, Scholtens, S, Nolte, IM, Richmond, RC, Relton, CL, Felix, JF, Duijts, L, Van Meurs, JB, Tiemeier, H, Jaddoe, VW, Wang, X, Corpeleijn, E & Snieder, H 2015, 'DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring', International Journal of Epidemiology, vol. 44, no. 4, pp. 1224-1237. https://doi.org/10.1093/ije/dyv048
Küpers LK, Xu X, Jankipersadsing SA, Vaez A, La Bastide-van Gemert S, Scholtens S et al. DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. International Journal of Epidemiology. 2015 Aug 1;44(4):1224-1237. https://doi.org/10.1093/ije/dyv048
Küpers, Leanne K. ; Xu, Xiaojing ; Jankipersadsing, Soesma A. ; Vaez, Ahmad ; La Bastide-van Gemert, Sacha ; 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. ; Wang, Xiaoling ; Corpeleijn, Eva ; Snieder, Harold. / DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. In: International Journal of Epidemiology. 2015 ; Vol. 44, No. 4. pp. 1224-1237.
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abstract = "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.",
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AU - Küpers, Leanne K.

AU - Xu, Xiaojing

AU - Jankipersadsing, Soesma A.

AU - Vaez, Ahmad

AU - La Bastide-van Gemert, Sacha

AU - Scholtens, Salome

AU - Nolte, Ilja M.

AU - Richmond, Rebecca C.

AU - Relton, Caroline L.

AU - Felix, Janine F.

AU - Duijts, Liesbeth

AU - Van Meurs, Joyce B.

AU - Tiemeier, Henning

AU - Jaddoe, Vincent W.

AU - Wang, Xiaoling

AU - Corpeleijn, Eva

AU - Snieder, Harold

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N2 - 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.

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