An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication

Jolien Rijlaarsdam, Irene Pappa, Esther Walton, Marian J Bakermans-Kranenburg, Viara R Mileva-Seitz, Ralph C A Rippe, Sabine J Roza, Vincent W V Jaddoe, Frank C Verhulst, Janine F Felix, Charlotte A M Cecil, Caroline L Relton, Tom R Gaunt, Wendy McArdle, Jonathan Mill, Edward D Barker, Henning Tiemeier, Marinus H van IJzendoorn

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Abstract

Prenatal maternal stress exposure has been associated with neonatal differential DNA methylation. However, the available evidence in humans is largely based on candidate gene methylation studies, where only a few CpG sites were evaluated. The aim of this study was to examine the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation using different methods. First, we conducted a meta-analysis and follow-up pathway analyses. Second, we used novel region discovery methods [i.e., differentially methylated regions (DMRs) analyses]. To this end, we used data from two independent population-based studies, the Generation R Study (n = 912) and the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 828), to (i) measure genome-wide DNA methylation in cord blood and (ii) extract a prenatal maternal stress composite. The meta-analysis (ntotal = 1,740) revealed no epigenome-wide (meta P <1.00e-07) associations of prenatal maternal stress exposure with neonatal differential DNA methylation. Follow-up analyses of the top hits derived from our epigenome-wide meta-analysis (meta P <1.00e-04) indicated an over-representation of the methyltransferase activity pathway. We identified no Bonferroni-corrected (P <1.00e-06) DMRs associated with prenatal maternal stress exposure. Combining data from two independent population-based samples in an epigenome-wide meta-analysis, the current study indicates that there are no large effects of prenatal maternal stress exposure on neonatal DNA methylation. Such replication efforts are essential in the search for robust associations, whether derived from candidate gene methylation or epigenome-wide studies.

Original languageEnglish
Pages (from-to)140-149
Number of pages10
JournalEpigenetics
Volume11
Issue number2
Early online date18 Feb 2016
DOIs
Publication statusPublished - Feb 2016

Keywords

  • Birth cohort
  • cord blood
  • DNA methylation
  • epigenome-wide association study (EWAS)
  • prenatal maternal stress

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    Rijlaarsdam, J., Pappa, I., Walton, E., Bakermans-Kranenburg, M. J., Mileva-Seitz, V. R., Rippe, R. C. A., Roza, S. J., Jaddoe, V. W. V., Verhulst, F. C., Felix, J. F., Cecil, C. A. M., Relton, C. L., Gaunt, T. R., McArdle, W., Mill, J., Barker, E. D., Tiemeier, H., & van IJzendoorn, M. H. (2016). An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication. Epigenetics, 11(2), 140-149. https://doi.org/10.1080/15592294.2016.1145329