title: 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.
authors.affiliation: National Institute of Environmental Health Sciences, NIH, U.S. Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
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authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, 3000 CA the Netherlands.
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authors.affiliation: University of Southern California, Los Angeles, CA 90032, USA.
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authors.affiliation: National Institute of Environmental Health Sciences, NIH, U.S. Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
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authors.affiliation: National Institute of Environmental Health Sciences, NIH, U.S. Department of Health and Human Services, Research Triangle Park, NC 27709, USA; Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC 27710, USA.
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authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; GRIAC Research Institute Groningen, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands.
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authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
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authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, 3000 CA the Netherlands; Division of Neonatology, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, 3000 CA, the Netherlands; Division of Respiratory Medicine, Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, 3000 CA, the Netherlands.
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authors.affiliation: Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, 3000 CA the Netherlands.
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mesh_terms: D001249:Asthma / Q000209:etiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002971:Cleft Lip / Q000209:etiology / Q000235:genetics; D002972:Cleft Palate / Q000209:etiology / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D011247:Pregnancy; D012907:Smoking / Q000009:adverse effects*; D044465:White People / Q000235:genetics