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Am J Hum Genet. 2016 Apr 7;98(4):680-96. doi: 10.1016/j.ajhg.2016.02.019. Epub 2016 Mar 31.

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

Author information

1
National Institute of Environmental Health Sciences, NIH, U.S. Department of Health and Human Services, Research Triangle Park, NC 27709, USA.
2
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.
3
Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California Berkeley, Berkeley, CA 94720-7360, USA.
4
Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
5
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
6
University of Southern California, Los Angeles, CA 90032, USA.
7
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.
8
MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
9
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.
10
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
11
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-2911, USA.
12
Department of Biological Sciences and Center for Human Health and the Environment, North Carolina State University, Raleigh, NC 27695-7633, USA.
13
Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
14
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm 141 83, Sweden.
15
Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
16
Sorbonne Universités, UPMC Univ Paris 06, INSERM, Pierre Louis Institute of Epidemiology and Public Health (IPLESP UMRS 1136), Epidemiology of Allergic and Respiratory Diseases Department (EPAR), Saint-Antoine Medical School, F75012 Paris, France.
17
Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN 38152, USA.
18
Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, Institut Albert Bonniot, Institut National de la Santé et de le Recherche Médicale, University of Grenoble Alpes, Centre Hospitalier Universitaire de Grenoble, F-38000 Grenoble, France.
19
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands.
20
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.
21
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.
22
Department of Global Public Health and Primary Care, University of Bergen, Bergen 5018, Norway.
23
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands; School of Medicine, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
24
Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
25
Department of Community and Family Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
26
Department of Pediatrics, Oslo University Hospital, Oslo 424, Norway.
27
Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3508 TD, the Netherlands.
28
Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain; Center for Genomic Regulation (CRG), Barcelona 08003, Spain.
29
INSERM, Epidemiological Research Unit on Perinatal Health and Women's and Children's Health, 75654 Paris, France.
30
Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA-Institut de Génomique, 91000 Evry, France.
31
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, 3000 CA, the Netherlands.
32
Division of Mental and Physical Health, Norwegian Institute of Public Health, Oslo 0403, Norway.
33
GRIAC Research Institute Groningen, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands.
34
Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
35
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
36
Epigenetics Group, International Agency for Research on Cancer (IARC), 69008 Lyon, France.
37
Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3508 TD, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3508 TD, the Netherlands.
38
Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003, Spain.
39
INSERM, UMR 1153, Early Origin of the Child's Health And Development (ORCHAD) Team, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS), Université Paris Descartes, 94807 Villejuif, France.
40
Department of Large Animal Clinical Sciences, Michigan State University, East Lansing, MI 48824, USA.
41
Centre National de la Recherche Scientifique-École Normale Supérieure de Lyon-Université Claude Bernard (Lyon 1), Université de Lyon, European Institute for Systems Biology and Medicine 69007 Lyon, France.
42
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
43
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3000 CA, the Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
44
School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
45
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
46
Obesity Prevention Program, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA 02215, USA.
47
Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Public Health Epidemiology, Unit of Chronic Disease Epidemiology, Swiss Tropical and Public Health Institute, Basel 4051, Switzerland; University of Basel, Basel 4001, Switzerland.
48
Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Sachs' Children's Hospital and Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm 171 77, Sweden.
49
Centre for Research in Environmental Epidemiology (CREAL), Barcelona 08003, Spain.
50
Faculty of Medicine, Clinical & Experimental Sciences, University of Southampton, Southampton SO16 6YD, UK; Faculty of Medicine, Human Development & Health, University of Southampton, Southampton SO16 6YD, UK.
51
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, 3000 CA the Netherlands.
52
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.
53
Faculty of Medicine, Clinical & Experimental Sciences, University of Southampton, Southampton SO16 6YD, UK.
54
Departments of Obstetrics and Gynecology and Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
55
Department of Medicine, University of California, San Francisco, San Francisco, CA 94143-2911, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143-2911, USA.
56
GRIAC Research Institute Groningen, University of Groningen, University Medical Center Groningen, 9700 RB, the Netherlands; Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen 9700 RB, the Netherlands.
57
National Institute of Environmental Health Sciences, NIH, U.S. Department of Health and Human Services, Research Triangle Park, NC 27709, USA. Electronic address: london2@niehs.nih.gov.

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.

PMID:
27040690
PMCID:
PMC4833289
DOI:
10.1016/j.ajhg.2016.02.019
[Indexed for MEDLINE]
Free PMC Article

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