Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns

Bonnie R. Joubert (), Herman T. den Dekker, Janine F. Felix, Jon Bohlin, Symen Ligthart, Emma Beckett, Henning Tiemeier, Joyce B. van Meurs, Andre G. Uitterlinden, Albert Hofman, Siri E. Håberg, Sarah E. Reese, Marjolein J. Peters, Bettina Kulle Andreassen, Eric A. P. Steegers, Roy M. Nilsen, Stein E. Vollset, Øivind Midttun, Per M. Ueland, Oscar H. Franco, Abbas Dehghan, Johan C. de Jongste, Michael C. Wu, Tianyuan Wang, Shyamal D. Peddada, Vincent W. V. Jaddoe, Wenche Nystad, Liesbeth Duijts and Stephanie J. London
Additional contact information
Bonnie R. Joubert: National Institute of Environmental Health Sciences, National Institutes of Health
Herman T. den Dekker: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
Janine F. Felix: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
Jon Bohlin: Norwegian Institute of Public Health
Symen Ligthart: Erasmus MC, University Medical Center Rotterdam
Emma Beckett: School of Environmental and Life Sciences, University of Newcastle
Henning Tiemeier: Erasmus MC, University Medical Center Rotterdam
Joyce B. van Meurs: Erasmus MC, University Medical Center Rotterdam
Andre G. Uitterlinden: Erasmus MC, University Medical Center Rotterdam
Albert Hofman: Erasmus MC, University Medical Center Rotterdam
Siri E. Håberg: Norwegian Institute of Public Health
Sarah E. Reese: National Institute of Environmental Health Sciences, National Institutes of Health
Marjolein J. Peters: Erasmus MC, University Medical Center Rotterdam
Bettina Kulle Andreassen: Institute of Clinical Medicine, University of Oslo
Eric A. P. Steegers: Erasmus MC, University Medical Center Rotterdam
Roy M. Nilsen: Centre for Clinical Research, Haukeland University Hospital
Stein E. Vollset: Norwegian Institute of Public Health
Øivind Midttun: Bevital A/S, Laboratoriebygget
Per M. Ueland: University of Bergen
Oscar H. Franco: Erasmus MC, University Medical Center Rotterdam
Abbas Dehghan: Erasmus MC, University Medical Center Rotterdam
Johan C. de Jongste: Erasmus MC, University Medical Center Rotterdam
Michael C. Wu: Public Health Sciences Program, Fred Hutchinson Cancer Research Center
Tianyuan Wang: National Institute of Environmental Health Sciences, National Institutes of Health
Shyamal D. Peddada: National Institute of Environmental Health Sciences, National Institutes of Health
Vincent W. V. Jaddoe: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
Wenche Nystad: Norwegian Institute of Public Health
Liesbeth Duijts: The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam
Stephanie J. London: National Institute of Environmental Health Sciences, National Institutes of Health

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: Abstract Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina’s HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.

Date: 2016
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DOI: 10.1038/ncomms10577

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