An Epigenome-Wide Association Meta-analysis of Prenatal Maternal Stress in Neonates: A Model Approach for Replication

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

doi:10.1080/15592294.2016.1145329

An Epigenome-Wide Association Meta-analysis of Prenatal Maternal Stress in Neonates: A Model Approach for Replication

Jolien Rijlaarsdam, Irene Pappa, Esther Walton, Marian Bakermans- Kranenburg, Viara Mileva-Seitz, Ralph Rippe, Sabine Roza, Vincent Jaddoe, Frank C Verhulst, Janine F. Felix, Charlotte Cecil, Caroline 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 language	English
Pages (from-to)	140-149
Journal	Epigenetics
Volume	11
Issue number	2
Early online date	22 Mar 2016
DOIs	https://doi.org/10.1080/15592294.2016.1145329
Publication status	Published - 2016

Keywords

DNA methylation
Prenatal stress
EPIGENOME-WIDE ASSOCIATION

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10.1080/15592294.2016.1145329

An epigenome-wide association_RIJLAARSDAM_Accepted15January2016_GOLD VoR (CC BY)Final published version, 1.25 MBLicence: CC BY

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Rijlaarsdam, J., Pappa, I., Walton, E., Bakermans- Kranenburg, M., Mileva-Seitz, V., Rippe, R., Roza, S., Jaddoe, V., Verhulst, F. C., Felix, J. F., Cecil, C., Relton, C., 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

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title = "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.",

keywords = "DNA methylation, Prenatal stress, EPIGENOME-WIDE ASSOCIATION",

author = "Jolien Rijlaarsdam and Irene Pappa and Esther Walton and {Bakermans- Kranenburg}, Marian and Viara Mileva-Seitz and Ralph Rippe and Sabine Roza and Vincent Jaddoe and Verhulst, {Frank C} and Felix, {Janine F.} and Charlotte Cecil and Caroline Relton and Gaunt, {Tom R.} and Wendy McArdle and Jonathan Mill and Barker, {Edward D.} and Henning Tiemeier and {van IJzendoorn}, {Marinus H}",

year = "2016",

doi = "10.1080/15592294.2016.1145329",

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pages = "140--149",

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Rijlaarsdam, J, Pappa, I, Walton, E, Bakermans- Kranenburg, M, Mileva-Seitz, V, Rippe, R, Roza, S, Jaddoe, V, Verhulst, FC, Felix, JF, Cecil, C, Relton, C, Gaunt, TR, McArdle, W, Mill, J , Barker, ED, Tiemeier, H & van IJzendoorn, MH 2016, 'An Epigenome-Wide Association Meta-analysis of Prenatal Maternal Stress in Neonates: A Model Approach for Replication', Epigenetics, vol. 11, no. 2, pp. 140-149. https://doi.org/10.1080/15592294.2016.1145329

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T1 - An Epigenome-Wide Association Meta-analysis of Prenatal Maternal Stress in Neonates

T2 - A Model Approach for Replication

AU - Rijlaarsdam, Jolien

AU - Pappa, Irene

AU - Walton, Esther

AU - Bakermans- Kranenburg, Marian

AU - Mileva-Seitz, Viara

AU - Rippe, Ralph

AU - Roza, Sabine

AU - Jaddoe, Vincent

AU - Verhulst, Frank C

AU - Felix, Janine F.

AU - Cecil, Charlotte

AU - Relton, Caroline

AU - Gaunt, Tom R.

AU - McArdle, Wendy

AU - Mill, Jonathan

AU - Barker, Edward D.

AU - Tiemeier, Henning

AU - van IJzendoorn, Marinus H

PY - 2016

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N2 - 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.

AB - 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.

KW - DNA methylation

KW - Prenatal stress

KW - EPIGENOME-WIDE ASSOCIATION

U2 - 10.1080/15592294.2016.1145329

DO - 10.1080/15592294.2016.1145329

M3 - Article

SN - 1559-2294

VL - 11

SP - 140

EP - 149

JO - Epigenetics

JF - Epigenetics

IS - 2

ER -

An Epigenome-Wide Association Meta-analysis of Prenatal Maternal Stress in Neonates: A Model Approach for Replication

Abstract

Keywords

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