An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: A model approach for replication
Open accessAbstract
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.
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A follow-up analysis of the top EWAS meta-analysis hits (p<.0001) in pathway databases indicated methyltransferase activity as the single most overrepresented molecular function.
“A follow-up analysis of the top EWAS metaanalysis hits (p<.0001) in pathway databases indicated methyltransferase activity as the single most overrepresented molecular function.”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Rijlaarsdam et al., 2016
A meta-analysis of two large EWAS sample sets (total n=1,740) found no epigenome-wide significant CpG methylation hit in cord blood extracted DNA associated with prenatal maternal stress.
“Strikingly, a meta-analysis of two large EWAS sample sets (total n=1,740) found no epigenome-wide significant CpG methylation hit in cord blood extracted DNA associated with prenatal maternal stress (Rijlaarsdam et al., 2016).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Rijlaarsdam et al., 2016
A clustering approach aimed at identifying differentially methylated regions found no Bonferroni-corrected cluster associated with prenatal maternal stress.
“A clustering approach aimed at identifying differentially methylated regions found no Bonferroni-corrected cluster associated with prenatal maternal stress”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Rijlaarsdam et al., 2016
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Additional file 1 of DNA methylation in cord blood in association with prenatal depressive symptoms
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Additional file 2 of DNA methylation in cord blood in association with prenatal depressive symptoms
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Additional file 3 of Prenatal risk factors and neonatal DNA methylation in very preterm infants
Camerota, M., Graw, S., Everson, T. M., McGowan, E. C., Hofheimer, J. A., O’Shea, T. M., Carter, B. S., Helderman, J. B., Check, J., Neal, C. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16607045
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Additional file 2 of Prenatal risk factors and neonatal DNA methylation in very preterm infants
Camerota, M., Graw, S., Everson, T. M., McGowan, E. C., Hofheimer, J. A., O’Shea, T. M., Carter, B. S., Helderman, J. B., Check, J., Neal, C. R., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16607042
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- Authors
- 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.
- Affiliations
- Leiden University (NL)
- Erasmus MC (NL)
- King's College London (GB)
- Centre for Child and Family Studies, Leiden University, Leiden, the Netherlands
- University of Bristol (GB)
- University of Exeter (GB)
- ORCID
- Venue
- Epigenetics
- Publisher
- Informa UK Limited
- Published
- 2016-02-01
- Volume
- 11
- Issue
- 2
- Pages
- 140-149
- ISSN
- 1559-2294 (ISSN-L)
- 1559-2308
- PMC
- PMC4846102
- OpenAlex
- W2276786836
- Cited by
- 97
- References
- 69
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 20 · 2020: 11 · 2019: 4 · 2018: 9 · 2017: 17 · 2016: 3
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Epigenetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (201310, 102215, 092731)
- European Commission (633595, HORIZON2020, 201310)
- University of Bristol (092731)
- ZonMw (VIDI 016. 136. 361, 100001003, 017.106.370,, 016.136.361, 024.001.003)
- Erasmus Universiteit Rotterdam
- Erasmus Medisch Centrum
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024‐001‐003, VIDI 016.136.361, 633595, 453.09.003, 017.106.370, 446-11-023, 016.136.361, 10.000.1003)
- Medical Research Council (633595, MC_PC_15018, 092731)
- Biotechnology and Biological Sciences Research Council (BB/I025263/1)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD068437)
- H2020 European Research Council (669249)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
- Keywords
- prenatal stress, umbilical cord blood, differentially methylated regions, replication, Generation R Study, Avon Longitudinal Study of Parents and Children
- MeSH terms
- Adult, Female, Fetal Blood, Humans, Longitudinal Studies, Male, Pregnancy, Prenatal Exposure Delayed Effects, Stress, Psychological, Maternal Exposure, CpG Islands, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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