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Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation

Molecular Psychiatry (2023)Cite this article

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Abstract

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

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Fig. 1: Geography of participating cohorts.
Fig. 2: Manhattan plots and related quantile–quantile plots showing sites of DNA methylation in cord blood.
Fig. 3: Forest plot from primary and secondary meta-analyses results.

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Code availability

The code used for this EWAS meta-analysis is available from the corresponding authors upon reasonable request.

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Acknowledgements

Acknowledgements and funding for each of the participating studies are listed in the Supplementary Methods sections.

Author information

Author notes

  1. These authors contributed equally: Anna Kotsakis Ruehlmann, Sara Sammallahti, Jari Lahti, Kelly J. Brunst.

Authors and Affiliations

  1. University of Cincinnati College of Medicine, Department of Environmental and Public Health Sciences, Cincinnati, OH, USA

    Anna Kotsakis Ruehlmann & Kelly J. Brunst

  2. Erasmus MC, University Medical Center Rotterdam, Department of Adolescent and Child Psychiatry and Psychology, Rotterdam, Netherlands

    Sara Sammallahti, Andrea P. Cortés Hidalgo & Charlotte A. M. Cecil

  3. The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands

    Sara Sammallahti, Andrea P. Cortés Hidalgo, Charlotte A. M. Cecil, Janine F. Felix & Rosa H. Mulder

  4. Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    Sara Sammallahti

  5. University of Michigan, School of Public Health, Department of Epidemiology, Ann Arbor, MI, USA

    Kelly M. Bakulski & John Dou

  6. Max Planck Institute of Psychiatry, Department of Translational Research in Psychiatry, Munich, Germany

    Elisabeth B. Binder, Cristiana Cruceanu, Darina Czamara & Linda Dieckmann

  7. University of Cape Town, Department of Psychiatry and Mental Health, Cape Town, South Africa

    Megan Loraine Campbell

  8. School of Psychology, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom

    Doretta Caramaschi & Gemma Sharp

  9. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom

    Doretta Caramaschi, Lotte C. Houtepen, Giulia Mancano & Gemma Sharp

  10. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Elena Colicino & Rosalind Wright

  11. International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany

    Linda Dieckmann

  12. Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    Janine F. Felix & Rosa H. Mulder

  13. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Josef Frank, Fabian Streit, Stephanie H. Witt & Lea Zillich

  14. Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway

    Siri E. Håberg & Christian M. Page

  15. Helmholtz Centre for Environmental Research - UFZ, Department of Environmental Immunology, Leipzig, Germany

    Gunda Herberth, Stefan Röder & Ana C. Zenclussen

  16. Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, 27709, NC, USA

    Thanh T. Hoang & Stephanie J. London

  17. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA

    Anke Hüls & Yining Zhang

  18. Gangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA

    Anke Hüls

  19. Department of Psychiatry and Mental Health, University of Cape Town, South Africa; and UCT Neuroscience Institute, Cape Town, South Africa

    Nastassja Koen & Dan J. Stein

  20. South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Cape Town, South Africa

    Nastassja Koen & Dan J. Stein

  21. Norwegian Institute of Public Health, Centre for Fertility and Health, Oslo, Norway

    Maria C. Magnus

  22. Department of Mathematics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway

    Christian M. Page

  23. University of Helsinki, Faculty of Medicine, Department of Psychology and Logopedics, Helsinki, Finland

    Katri Räikkönen, Johanna Tuhkanen & Jari Lahti

  24. University of California-Davis, School of Medicine, Department of Public Health Sciences, Davis, CA, USA

    Rebecca J. Schmidt

  25. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    Tabea S. Send

  26. Department of Paediatrics & Child Health & SA-MRC Unit on Child & Adolescent Health, University of Cape Town, Cape Town, South Africa

    Heather J. Zar

  27. Kravis Children’s Hospital, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Rosalind Wright

  28. Institute for Exposomic Research, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Rosalind Wright

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  1. Anna Kotsakis Ruehlmann
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  14. Janine F. Felix
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Contributions

All authors made substantial contributions to conception, design, acquisition of data, and/or analysis and interpretation of data. AKR, SS, APCH, JL and KJB drafted/revised the article. All other authors revised the manuscript critically for important intellectual content and gave final approval of the current version of this article.

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Correspondence to Kelly J. Brunst.

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Kotsakis Ruehlmann, A., Sammallahti, S., Cortés Hidalgo, A.P. et al. Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02010-5

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