Interactive effects of genotype with prenatal stress on DNA methylation at birth

Rosa H Mulder; Vilte Baltramonaityte; Serena Defina; Matthew Suderman; Marco P. Boks; Esther Walton; Charlotte A.M. Cecil; Janine F Felix

doi:10.1038/s41380-025-03312-6

Interactive effects of genotype with prenatal stress on DNA methylation at birth

Rosa H Mulder
, Vilte Baltramonaityte
, Serena Defina
, Matthew Suderman
, Marco P. Boks
, Esther Walton
, Charlotte A.M. Cecil
, Janine F Felix

Erasmus University Medical Center
University of Bristol
Amsterdam UMC
Dimence Group
King's College London
Leiden University Medical Center

Research output: Contribution to journal › Article › peer-review

3 Citations (SciVal)

Abstract

Intrauterine stress exposure is associated with offspring health. DNA methylation (DNAm) is a putative underlying mechanism, but large population-based studies reported limited associations between prenatal stress and DNAm. Recent research has shown that environmental factors in interaction with genetic variants are better predictors of DNAm than environment or genotype alone. We investigated whether interactions of maternal prenatal stress with genetic variants are associated with DNAm at birth. We examined 2963 mother-child pairs from the population-based Generation R Study and Avon Longitudinal Study of Parents and Children, using a harmonized, comprehensive cumulative prenatal stress measure. We tested genome-wide genotype-by-prenatal stress interactions on epigenome-wide DNAm (GxEmodel), and models including only genetic variants (Gmodel) or prenatal stress (Emodel) as predictors. Follow-up analyses included Gene Ontology analyses and mediation analyses of prenatal alcohol intake, smoking, gestational age, and birth weight. We report two independent gene-by-prenatal-stress interactions on DNAm after multiple testing correction, including five genetic variants in CHD2 and ORC5, and two DNAm sites in EPPK1. By comparison, the Gmodel showed 691,202 associations and the Emodel showed three associations in genes AHRR, GFI1, and MYO1G, which could largely be explained by prenatal smoking. Genes linked to suggestive GxEmodel results were often involved in neuronal development. Our results provide some support of interaction of prenatal stress with the child’s genome on DNAm of genes related to neuronal development. Based on these models, genetic main effects on DNA methylation at birth were much more abundant than gene-by-prenatal stress interactions were.

Original language	English
Number of pages	11
Journal	Molecular Psychiatry
DOIs	https://doi.org/10.1038/s41380-025-03312-6
Publication status	Published - 24 Oct 2025

Acknowledgements

The Generation R Study is conducted by Erasmus MC, University Medical Center Rotterdam in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, Rotterdam, the Rotterdam Homecare Foundation, Rotterdam and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives and pharmacies in Rotterdam. The generation and management of the Illumina 450 K methylation array data (EWAS data) for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Netherlands. We thank Mr. Michael Verbiest, Ms. Mila Jhamai, Ms. Sarah Hunter, Mr. Marijn Verkerk and Dr. Lisette Stolk for their help in creating the EWAS database. We thank Dr. A. Teumer for his work on the quality control and normalization scripts. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses.

Funding

The general design of The Generation R Study was made possible by financial support from Erasmus MC, Rotterdam, Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMW), the Netherlands Organization for Scientific Research (NWO), the Ministry of Health, Welfare and Sport and the Ministry of Youth and Families. High performance computing for data analysis was provided by the Dutch Organization for Scientific Research (NWO 2021.042, “Snellius” www.surf.nl). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. Genomewide genotyping data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. DNA methylation data generation was funded by the Biotechnology and Biological Sciences Research Council (BBSRC; grant numbers BBI025751/1 and BB/I025263/1) and the Medical Research Council (MRC; grand numbers MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). A comprehensive lists of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This publication is the work of the authors and Esther Walton will serve as guarantor for the contents of this paper. The work of RHM, VB, SD, EW, CAMC and JFF is supported by the European Union’s Horizon 2020 Research and Innovation Programme (RHM, VB, SD, EW, CAMC and JFF: EarlyCause, grant agreement No 848158; CAMC and JFF: STAGE; STAGE has received funding from the European Union’s Horizon Europe Research and Innovation Programme under grant agreement n° 101137146. UK participants in Horizon Europe Project STAGE are supported by UKRI grant numbers 10112787 (Beta Technology), 10099041 (University of Bristol) and 10109957 (Imperial College London)). CAMC is also supported by the European Union’s HorizonEurope Research and Innovation Programme (FAMILY, grant agreement No 101057529; HappyMums, grant agreement No 101057390) and the European Research Council (TEMPO; grant agreement No 101039672). EW also received funding from UK Research and Innovation (UKRI) under the UK government’s Horizon Europe / ERC Frontier Research Guarantee [BrainHealth, grant number EP/Y015037/1]. This research was conducted while CAMC was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research.

Funders	Funder number
UK Research & Innovation	EP/Y015037/1

Access to Document

10.1038/s41380-025-03312-6Licence: CC BY

Cite this

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title = "Interactive effects of genotype with prenatal stress on DNA methylation at birth",

abstract = "Intrauterine stress exposure is associated with offspring health. DNA methylation (DNAm) is a putative underlying mechanism, but large population-based studies reported limited associations between prenatal stress and DNAm. Recent research has shown that environmental factors in interaction with genetic variants are better predictors of DNAm than environment or genotype alone. We investigated whether interactions of maternal prenatal stress with genetic variants are associated with DNAm at birth. We examined 2963 mother-child pairs from the population-based Generation R Study and Avon Longitudinal Study of Parents and Children, using a harmonized, comprehensive cumulative prenatal stress measure. We tested genome-wide genotype-by-prenatal stress interactions on epigenome-wide DNAm (GxEmodel), and models including only genetic variants (Gmodel) or prenatal stress (Emodel) as predictors. Follow-up analyses included Gene Ontology analyses and mediation analyses of prenatal alcohol intake, smoking, gestational age, and birth weight. We report two independent gene-by-prenatal-stress interactions on DNAm after multiple testing correction, including five genetic variants in CHD2 and ORC5, and two DNAm sites in EPPK1. By comparison, the Gmodel showed 691,202 associations and the Emodel showed three associations in genes AHRR, GFI1, and MYO1G, which could largely be explained by prenatal smoking. Genes linked to suggestive GxEmodel results were often involved in neuronal development. Our results provide some support of interaction of prenatal stress with the child{\textquoteright}s genome on DNAm of genes related to neuronal development. Based on these models, genetic main effects on DNA methylation at birth were much more abundant than gene-by-prenatal stress interactions were.",

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AU - Mulder, Rosa H

AU - Baltramonaityte, Vilte

AU - Defina, Serena

AU - Suderman, Matthew

AU - Boks, Marco P.

AU - Walton, Esther

AU - Cecil, Charlotte A.M.

AU - Felix, Janine F

PY - 2025/10/24

Y1 - 2025/10/24

N2 - Intrauterine stress exposure is associated with offspring health. DNA methylation (DNAm) is a putative underlying mechanism, but large population-based studies reported limited associations between prenatal stress and DNAm. Recent research has shown that environmental factors in interaction with genetic variants are better predictors of DNAm than environment or genotype alone. We investigated whether interactions of maternal prenatal stress with genetic variants are associated with DNAm at birth. We examined 2963 mother-child pairs from the population-based Generation R Study and Avon Longitudinal Study of Parents and Children, using a harmonized, comprehensive cumulative prenatal stress measure. We tested genome-wide genotype-by-prenatal stress interactions on epigenome-wide DNAm (GxEmodel), and models including only genetic variants (Gmodel) or prenatal stress (Emodel) as predictors. Follow-up analyses included Gene Ontology analyses and mediation analyses of prenatal alcohol intake, smoking, gestational age, and birth weight. We report two independent gene-by-prenatal-stress interactions on DNAm after multiple testing correction, including five genetic variants in CHD2 and ORC5, and two DNAm sites in EPPK1. By comparison, the Gmodel showed 691,202 associations and the Emodel showed three associations in genes AHRR, GFI1, and MYO1G, which could largely be explained by prenatal smoking. Genes linked to suggestive GxEmodel results were often involved in neuronal development. Our results provide some support of interaction of prenatal stress with the child’s genome on DNAm of genes related to neuronal development. Based on these models, genetic main effects on DNA methylation at birth were much more abundant than gene-by-prenatal stress interactions were.

AB - Intrauterine stress exposure is associated with offspring health. DNA methylation (DNAm) is a putative underlying mechanism, but large population-based studies reported limited associations between prenatal stress and DNAm. Recent research has shown that environmental factors in interaction with genetic variants are better predictors of DNAm than environment or genotype alone. We investigated whether interactions of maternal prenatal stress with genetic variants are associated with DNAm at birth. We examined 2963 mother-child pairs from the population-based Generation R Study and Avon Longitudinal Study of Parents and Children, using a harmonized, comprehensive cumulative prenatal stress measure. We tested genome-wide genotype-by-prenatal stress interactions on epigenome-wide DNAm (GxEmodel), and models including only genetic variants (Gmodel) or prenatal stress (Emodel) as predictors. Follow-up analyses included Gene Ontology analyses and mediation analyses of prenatal alcohol intake, smoking, gestational age, and birth weight. We report two independent gene-by-prenatal-stress interactions on DNAm after multiple testing correction, including five genetic variants in CHD2 and ORC5, and two DNAm sites in EPPK1. By comparison, the Gmodel showed 691,202 associations and the Emodel showed three associations in genes AHRR, GFI1, and MYO1G, which could largely be explained by prenatal smoking. Genes linked to suggestive GxEmodel results were often involved in neuronal development. Our results provide some support of interaction of prenatal stress with the child’s genome on DNAm of genes related to neuronal development. Based on these models, genetic main effects on DNA methylation at birth were much more abundant than gene-by-prenatal stress interactions were.

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Interactive effects of genotype with prenatal stress on DNA methylation at birth

Abstract

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BrainHealth - Decoding life course pathways of mental ageing - Frontier Research Guarantee

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Interactive effects of genotype with prenatal stress on DNA methylation at birth

Abstract

Acknowledgements

Funding

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BrainHealth - Decoding life course pathways of mental ageing - Frontier Research Guarantee

EarlyCause

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