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

doi:10.1080/15592294.2016.1145329

Abstract

ABSTRACTPrenatal 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.

Highlights

Exposure to maternal stress in utero can negatively affect development in later life.[1,2,3,4] For example, prenatal exposure to maternal depressive symptoms[5] and contextual stress[6] have been associated with increased risk for offspring problem behavior, beyond variance attributable to postnatal exposures
Both the individual study epigenome-wide analyses and the metaanalysis revealed no epigenome-wide (Bonferronior FDR-corrected P-value) association of the prenatal maternal stress exposure (PMSE) score with neonatal DNA methylation
All top CpG probes identified by the random-effects epigenomewide association study (EWAS) meta-analysis are presented in the Supplementary Material (Table S6)

Summary

Introduction

Exposure to maternal stress in utero can negatively affect development in later life.[1,2,3,4] For example, prenatal exposure to maternal depressive symptoms[5] and contextual stress (e.g., economic disadvantage)[6] have been associated with increased risk for offspring problem behavior, beyond variance attributable to postnatal exposures. The vast majority of studies investigating the association between prenatal exposure to maternal stress and offspring methylation at birth have focused on candidate genes.[9,10,11,12,13,14] For example, Cecil et al.[9] demonstrated that neonates who were exposed to maternal stress (e.g., maternal psychopathology, criminal behaviors, substance use) in the prenatal period had higher methylation levels of the oxytocin receptor (OXTR) gene than non-exposed neonates. The findings of these candidate gene studies support the Supplemental data for this article can be accessed on the publisher’s website

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Conclusion