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

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.

Methylation matters: FK506 binding protein 51 (FKBP5) methylation moderates the associations ofFKBP5genotype and resistant attachment with stress regulation

“…Third, most studies on DNA methylation in the domain of developmental psychopathology are severely underpowered with potentially quite a few false positive findings that may turn out to be impossible to replicate. In an epigenome-wide study of a large Generation R sample of 912 families, we were unable to replicate our suggestive findings on the association between maternal prenatal stress and neonatal DNA methylation in another large sample of 828 families, the Avon Longitudinal Study of Parents and Children, ALSPAC (Rijlaarsdam et al, 2016). Our current study on almost 300 children is one of the largest candidate-(epi)gene studies on DNA methylation, but still underpowered in view of the Gene × Methylation × Environment (G × M × E, Van IJzendoorn et al, 2010;Bakermans-Kranenburg & Van IJzendoorn, 2015) three-way interactions.…”

“…Our current study on almost 300 children is one of the largest candidate-(epi)gene studies on DNA methylation, but still underpowered in view of the Gene × Methylation × Environment (G × M × E, Van IJzendoorn et al, 2010;Bakermans-Kranenburg & Van IJzendoorn, 2015) three-way interactions. Independent replication is therefore badly needed (Rijlaarsdam et al, 2016).It is somewhat assuring that our findings are in line with Klengel et al (2013), who found an association between FKBP5 methylation and HPA axis regulation, particularly in FKBP5 rs1360780 T allele carriers. However, their sample size for these analyses was only 76 with 30 highly traumatized cases and 46 controls in one of their central epigenetic analyses.…”

“…Our current study on almost 300 children is one of the largest candidate-(epi)gene studies on DNA methylation, but still underpowered in view of the Gene × Methylation × Environment (G × M × E, Van IJzendoorn et al, 2010;Bakermans-Kranenburg & Van IJzendoorn, 2015) three-way interactions. Independent replication is therefore badly needed (Rijlaarsdam et al, 2016).…”

Epigenetics: from the past to the present

“…The maternal stress covered aspects as stress due to personal and family circumstances, financial difficulties, psychopathologies and substance abuse. However, this investigation did not find evidence supporting differential DNA methylation associated to the evaluated factors (Rijlaarsdam et al 2016). In another important research, Gruzieva et al (2016) investigated the effect of maternal exposure during pregnancy to air pollution (NO 2 ), in DNA methylation of cord blood.…”

“…These results show a broader view of the role of maternal folate in the epigenome development and disease risk in the offspring (Joubert, den Dekker, et al 2016). Rijlaarsdam et al (2016) evaluated the association between prenatal exposure to maternal stress and offspring genome-wide cord blood methylation (450 K) in more than 1700 neonates and their mothers. The maternal stress covered aspects as stress due to personal and family circumstances, financial difficulties, psychopathologies and substance abuse.…”