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Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

Author

Listed:
  • Lotte C. Houtepen

    (Brain Center Rudolf Magnus, University Medical Center Utrecht)

  • Christiaan H. Vinkers

    (Brain Center Rudolf Magnus, University Medical Center Utrecht)

  • Tania Carrillo-Roa

    (Max Planck Institute of Psychiatry)

  • Marieke Hiemstra

    (Research Centre Adolescent Development, University Utrecht (UU))

  • Pol A. van Lier

    (VU University)

  • Wim Meeus

    (Research Centre Adolescent Development, University Utrecht (UU)
    Tilburg University 5000 LE)

  • Susan Branje

    (Research Centre Adolescent Development, University Utrecht (UU))

  • Christine M. Heim

    (Institute of Medical Psychology, Charité-University Medicine, Medical Centre, 10117
    Pennsylvania State University, University Park)

  • Charles B. Nemeroff

    (Leonard M. Miller School of Medicine, University of Miami)

  • Jonathan Mill

    (University of Exeter Medical School, University of Exeter
    Institute of Psychiatry, Psychology & Neuroscience, King's College London)

  • Leonard C. Schalkwyk

    (School of Biological Sciences, University of Essex)

  • Menno P. Creyghton

    (Hubrecht Institute-KNAW and University Medical Center Utrecht (UMCU))

  • René S. Kahn

    (Brain Center Rudolf Magnus, University Medical Center Utrecht)

  • Marian Joëls

    (Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU))

  • Elisabeth B. Binder

    (Max Planck Institute of Psychiatry
    Emory University School of Medicine)

  • Marco P. M. Boks

    (Brain Center Rudolf Magnus, University Medical Center Utrecht)

Abstract

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10−6). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability.

Suggested Citation

  • Lotte C. Houtepen & Christiaan H. Vinkers & Tania Carrillo-Roa & Marieke Hiemstra & Pol A. van Lier & Wim Meeus & Susan Branje & Christine M. Heim & Charles B. Nemeroff & Jonathan Mill & Leonard C. Sc, 2016. "Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10967
    DOI: 10.1038/ncomms10967
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    Cited by:

    1. Kobe Ridder & Huiwen Che & Kaat Leroy & Bernard Thienpont, 2024. "Benchmarking of methods for DNA methylome deconvolution," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Yinan Lin & Zijian Guo & Baoluo Sun & Zhenhua Lin, 2025. "Testing high-dimensional mediation effect with arbitrary exposure–mediator coefficients," TEST: An Official Journal of the Spanish Society of Statistics and Operations Research, Springer;Sociedad de Estadística e Investigación Operativa, vol. 34(3), pages 530-579, September.
    3. Laurens Holmes & Emily Shutman & Chinacherem Chinaka & Kerti Deepika & Lavisha Pelaez & Kirk W. Dabney, 2019. "Aberrant Epigenomic Modulation of Glucocorticoid Receptor Gene (NR3C1) in Early Life Stress and Major Depressive Disorder Correlation: Systematic Review and Quantitative Evidence Synthesis," IJERPH, MDPI, vol. 16(21), pages 1-17, November.
    4. Conching, Andie Kealohi Sato & Thayer, Zaneta, 2019. "Biological pathways for historical trauma to affect health: A conceptual model focusing on epigenetic modifications," Social Science & Medicine, Elsevier, vol. 230(C), pages 74-82.
    5. Cai, Xizhen & Zhu, Yeying & Huang, Yuan & Ghosh, Debashis, 2022. "High-dimensional causal mediation analysis based on partial linear structural equation models," Computational Statistics & Data Analysis, Elsevier, vol. 174(C).

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