Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation

- Impact on birth weight of maternal.
- Background: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy.
- One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood.
- and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight.
- The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels..
- Methods: Methylation levels in the cord blood of 313 newborns were determined using the Illumina.
- To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites.
- Results: Following quality control, 282 newborns eventually remained in the analysis.
- After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top “ smoking methylation pattern ” genes AHRR , MYO1G , GFI1 , CYP1A1 , and CNTNAP2 .
- The effect of maternal smoking on birth weight was partly mediated by the.
- Full list of author information is available at the end of the article.
- 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0.
- Conclusion: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight.
- The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence.
- Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight..
- Despite the efforts of advisory boards to inform women of the risk to the developing fetus, around 10% of mothers continue to smoke during preg- nancy [https://www.cdc.gov/prams.
- Previous research has identified associations between maternal smoking during pregnancy and a range of health problems in the offspring [2, 3].
- One of the most widely reported effects is low birth weight [4 – 6].
- Low birth weight has in turn been associated with various long-term health problems in adulthood.
- Low birth weight has also been associated with psychiatric disorders, such as schizophrenia and depression [12, 13]..
- A number of studies have also investigated the impact of maternal smoking during pregnancy on methylation patterns in the offspring.
- Previous authors have formulated the hypothesis that maternal smoking impacts birth weight via smoking- induced DNA methylation.
- differential methylation functions as a mediator, i.e., a variable that accounts for part of the relation between the predictor and the criterion [35, 36].
- Initial analyses to determine whether DNA methylation mediates between maternal smoking and birth weight have already been performed.
- The aims of the present study were to replicate the previously reported mediating effects of methylation on the association between maternal smoking and birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific.
- A detailed description of the POSEIDON study is provided elsewhere [41].
- The study protocol was approved by the Ethics Committee of the Medical Faculty Mannheim of the University of Heidelberg, and the study was con- ducted in accordance with the Declaration of Helsinki..
- Exclusion criteria in the offspring were: birth weight <1.500 g.
- Sociodemographic data are presented in the supplement (Additional file 1:.
- For the purposes of the present analyses, the women were divided into two subgroups: smokers and non-smokers.
- Probes were excluded if any of the following criteria were met: beadcount <3.
- Detected batch effects were then removed using the ComBat procedure, as implemented in the sva package [54].
- Cell type composition was estimated using the Houseman reference based method, as implemented in the minfi package [55].
- Association testing for methylation levels was performed using general linear models as implemented in the R-package limma.
- Gestational age, sex of the new- born, and parental height were included as covariates, since research has shown that these factors impact birth weight [56].
- Sites showing significant association with smoking (FDR<0.05) were then used to test whether methylation levels partly mediate the effects of maternal smoking on birth weight.
- The same possible confounders as named above were included as additional covariates in the mediator and outcome regression models (gesta- tional age, sex of the newborn, parental height, maternal age, cell type composition.
- Data on the trait “birth weight” were obtained from the EGG Consortium via the UK Biobank Resource.
- Gene-based analysis was performed using the ´birth weight summary statistic data 2016´ (file: BW3_EUR_.
- birth-weight-2016.html) and MAGMA v1.06[59].
- The applied linkage disequilibrium (LD) structure was that of the 1000 Genomes project (http://www.internationalgen- ome.org/data).
- The general characteristics of the partici- pants included in the present study are provided in Additional file 1: Table S1..
- Impact of maternal smoking on birth weight.
- a) The average difference in birth weight between the smoking and non-smoking groups was 209g.
- The newborns of smokers had a mean birth weight of 3,267g.
- b) In female newborns (n=144), the average birth weight was 189g lower in the smoking subgroup compared to the non-smoking subgroup, i.e., birth weight was 5.6% lower when mothers smoked..
- In male newborns ( n =138), the average birth weight was significantly lower by 242g in the smoking subgroup compared to the non-smoking subgroup, i.e., birth weight was 6.7% lower when mothers smoked (see Table 1)..
- Following correction for multiple testing, a total of 30 CpG sites showed significant differential methylation in the smoking subgroup (see Table 2).
- Of the 30 CpG sites found differentially methylated after maternal smoking in our sample, the following were found to mediate the effect of maternal smoking on birth weight: cg25325512 (PIM1, p=0.005).
- Sex-specific analyses for these three CpG sites re- vealed that cg25949550 (CNTNAP2, p=0.022) mediated the effect of maternal smoking on birth weight in male newborns (see Table 3)..
- Gene-based analysis of EGG Consortium GWAS results In the gene-based-analysis, PIM1, CNTNAP2, and ITGB7 were tested for association with birth weight.
- Single marker p-values of the SNPs at the ITGB7 locus are listed in Additional file 1: Table S2..
- The aims of the present study were to replicate the finding that the association between maternal smoking and birth weight is mediated by methylation, and to investigate whether the observed mediation effects are sex-specific.
- Table 1 Average birth weight of newborns.
- Birth weight 3,267g (437) a 3,476g (455) a b 0.03.
- Birth weight females 3,172g (500) a 3,361g (428) a b 0.23.
- Birth weight males 3,355g (367) a 3,597g (452) a b 0.04.
- Mediation analysis of the 30 CpG sites revealed that CpG sites in the genes PIM1, CNTNAP2, and ITGB7 mediated the effect of maternal smoking on birth weight in the complete sample.
- c Total effect of smoking on birth weight (ACME+ADE).
- d Association between birth weight and methylation after adjustment for smoking and covariates.
- e Association between birth weight and sustained maternal smoking after adjustment for methylation and covariates.
- f Association between maternal smoking and birth weight after adjustment for covariates, irrespective of methylation levels.
- The Contactin Associated Protein-Like 2 gene (CNTNAP2) encodes a member of the neurexin family, whose members function as cell adhesion molecules and receptors in the nervous system of vertebrates.
- The methylation level of the mediating CpG cg25949550 in CNTNAP2 is lower in infants whose mothers smoked during pregnancy, presumably leading to higher gene ex- pression.
- The Integrin Subunit Beta 7 gene (ITGB7) encodes a pro- tein that is a member of the integrin superfamily..
- The genes PIM1, CNTNAP2, and ITGB7 were not implicated in previous EWAS of birth weight [69–71]..
- However, in a gene-based analysis of genetic data obtained from a genome-wide association analysis of birth weight by the EGG Consortium [58], the present authors found that ITGB7 was strongly associated with birth weight (p=4, 2x10 -7.
- In contrast to previous studies, parental height was included as a covariate in the present analyses, as it had a pronounced influence on birth weight in our study..
- Performance of the analysis without this covariate did indeed obtain 45 rather than 30CpG sites associated with smoking.
- The present study had several limitations in terms of the investigated smoking phenotype.
- This may have led to an underestimation of the number of smoking mothers, and thus to an underestimation of the direct effect, and an overestimation of the mediation effect, of smoking..
- How- ever, unreliable self-reporting of smoking status in the present cohort is unlikely for two reasons.
- Second, the direct effect of smoking on birth weight in the present cohort (average reduction in birth weight of ~200g) was more pro- nounced than that reported in the MoBa study of Valeri et al (~90g).
- The present study supports reported findings that DNA methylation may represent a biological mechanism through which maternal smoking impacts birth weight..
- Unsurprisingly, this effect may be sex-dependent, as sug- gested for the first time in the present analyses.
- Further studies are warranted to investigate the role of the identified differentially methylated loci in mediating the as- sociation between maternal smoking during pregnancy and birth weight, and their role in determining offspring pheno- types in later life..
- The Supplementary Text includes supplementary information with respect to methods (mediation analysis), a description of the differentially methylated genes, Figure S1.
- We are very grateful for the essential contributions of the midwives, and would like to thank all families for their participation..
- This work was supported by the a Era-Net Neuron grant to M.R., M.D., and M.Lt., the German Research Foundation [DFG.
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