DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

Abstract

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

The Neonatal Methylome as a Gatekeeper in the Trajectory to Childhood Asthma

“…Importantly, 6 genes (ENOSF1, HOXB2, IL32, NLRP2, PASK, and TDRD9) exhibited significant CpG-transcript relationships in both adults and children. It is also worth emphasizing that the most significant hit of this study (cg05575921; AHRR) was also the top hit in other studies that have investigated the association between childhood DNA methylation and maternal smoking during pregnancy [31]. In combination, these data suggest that prenatal exposures may influence the epigenetic trajectory to asthma and elicit responses that persist into childhood.…”

“…Of the 3,932 CpG sites that remained associated with prenatal smoke exposure after adjusting for cell type, the vast majority (2,965 CpGs) had not been previously reported to be linked to maternal smoking during pregnancy [31]. When these novel CpGs were interrogated for their relationship with gene expression in adults, 254 unique CpGs were found to be significantly associated with the expression of a transcript located within 250 kb.…”

“…A follow-up meta-analysis addressed these issues in a much larger population (n=6,685 neonates) [31]. Of the 3,932 CpG sites that remained associated with prenatal smoke exposure after adjusting for cell type, the vast majority (2,965 CpGs) had not been previously reported to be linked to maternal smoking during pregnancy [31].…”

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study

“…In a more recent study, the authors identified numerous loci associated with maternal smoking during pregnancy in a genome-wide consortium meta-analysis and found substantial persistence of such effects in later childhood. 18 Zeilinger et al 19 conducted an epigenomewide study comparing methylation levels among current, former, and never smokers in a population-based panel, and found widespread differences in the degree of site-specific methylation as a function of tobacco smoking. Moreover, they observed that the most significant associations with smoking were for DNA methylation sites in AHRR.…”

Cannabis use by women during pregnancy does not influence infant DNA methylation of the dopamine receptor DRD4

“…Most studies to date do not differentiate cannabis from tobacco use, despite the fact that cannabis is often smoked together with tobacco, and tobacco has similar effects on infant health. This is problematic because maternal smoking during pregnancy has been consistently shown to influence infant DNA methylation in peripheral tissue and to mediate the association between prenatal exposure (21,22) and infant birth weight (23). Furthermore, a very recent study found that cannabis alone had no independent effect on perinatal outcomes, but augmented the risk associated with tobacco smoking (24).…”