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

Authors

Bonnie R. Joubert, National Institute of Environmental Health Sciences (NIEHS)
Janine F. Felix, Erasmus MC
Paul Yousefi, Center for Environmental Research and Children's HealthFollow
Kelly M. Bakulski, Johns Hopkins Bloomberg School of Public HealthFollow
Allan C. Just, Icahn School of Medicine at Mount Sinai
Carrie Breton, University of Southern CaliforniaFollow
Sarah E. Reese, National Institute of Environmental Health Sciences (NIEHS)
Christina A. Markunas, National Institute of Environmental Health Sciences (NIEHS)
Rebecca C. Richmond, University of Bristol
Cheng Jian Xu, Universitair Medisch Centrum GroningenFollow
Leanne K. Küpers, Universitair Medisch Centrum Groningen
Sam S. Oh, University of California, San Francisco
Cathrine Hoyo, NC State University
Olena Gruzieva, Karolinska Institutet
Cilla Söderhäll, Karolinska Institutet
Lucas A. Salas, Instituto de Salud Global de Barcelona
Nour Baïz, Sorbonne Universite
Hongmei Zhang, University of MemphisFollow
Johanna Lepeule, Universite Grenoble Alpes
Carlos Ruiz, Instituto de Salud Global de Barcelona
Symen Ligthart, Erasmus MC
Tianyuan Wang, National Institute of Environmental Health Sciences (NIEHS)
Jack A. Taylor, National Institute of Environmental Health Sciences (NIEHS)
Liesbeth Duijts, Erasmus MC
Gemma C. Sharp, University of Bristol
Soesma A. Jankipersadsing, Universitair Medisch Centrum Groningen
Roy M. Nilsen, Universitetet i Bergen
Ahmad Vaez, Universitair Medisch Centrum Groningen
M. Daniele Fallin, Johns Hopkins Bloomberg School of Public Health
Donglei Hu, University of California, San Francisco
Augusto A. Litonjua, Brigham and Women's Hospital
Bernard F. Fuemmeler, Duke University School of Medicine
Karen Huen, Center for Environmental Research and Children's Health

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.

Publication Title

American Journal of Human Genetics

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