Identification of DNA Methylation Changes in Newborns Related to Maternal Smoking during Pregnancy

Christina A. Markunas,1* Zongli Xu,1* Sophia Harlid,2 Paul A. Wade,2 Rolv T. Lie,3,4 Jack A. Taylor,1,2 and Allen J. Wilcox1

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1Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, North Carolina, USA; 2Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, North Carolina, USA; 3Department of Global Public Health and Primary Care, University of Bergen, Norway; 4Medical Birth Registry of Norway, Norwegian Institute of Public Health, Bergen, Norway. *These authors contributed equally to this work.

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Abstract

Background: Maternal smoking during pregnancy is associated with significant infant morbidity and mortality, and may influence later disease risk. One mechanism by which smoking (and other environmental factors) might have long-lasting effects is through epigenetic modifications such as DNA methylation.

Objectives: To conduct an epigenome-wide association study (EWAS) investigating alterations in DNA methylation in infants exposed in utero to maternal tobacco smoke, using the Norway Facial Clefts Study.

Methods: The Illumina HumanMethylation450 BeadChip was used to assess DNA methylation in whole blood from 889 infants shortly after delivery. Out of 889 mothers, 287 reported smoking – twice as many smokers as in any previous EWAS of maternal smoking. CpG sites related to maternal smoking during the first trimester were identified using robust linear regression.

Results: We identified 185 CpGs with altered methylation in infants of smokers at genome-wide significance (q-value < 0.05; Mean Δβ= +/- 2%). These correspond to 110 gene regions, of which 7 have been previously reported and 10 are newly confirmed using publically-available results. Among these 10 the most noteworthy are FRMD4A, ATP9A, GALNT2, and MEG3, implicated in processes related to nicotine dependence, smoking cessation, and placental and embryonic development.

Conclusions: Our study identified 10 genes with newly established links to maternal smoking. Further, we note differences between smoking-related methylation changes in newborns and adults, suggesting possible distinct effects of direct versus indirect tobacco-smoke exposure as well as potential differences due to age. Further work would be needed to determine if these small changes in DNA methylation are biologically or clinically relevant. The methylation changes identified in newborns may mediate the association between in utero maternal smoking exposure and later health outcomes.