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Author Notes:

Correspondence and requests for materials should be addressed to L.C.H. (email: L.Houtepen@umcutrecht.nl) or to M.P.M.B. (email: M.P.M.Boks@umcutrecht.nl).

Author contributions and competing financial interests are listed in the full text of the article.

We acknowledge Ruben Van ‘t Slot for his practical assistance with the methylation analysis, Dr Eilis Hannon for her invaluable assistance with the blood–brain correlations and Josine Vaes for her help with the identification of the childhood trauma studies in the literature.


Research Funding:

The RADAR cohort has been financially supported by main grants from the Netherlands Organisation for Scientific Research to RADAR PI’s and the CID consortium.

The blood replication sample study was supported by the Silvio O. Conte Center for the Psychobiology of Major Psychiatric Disorders (National Institutes of Health Grant MH58922).

C.H.V. and M.P.M.B. acknowledge a seeding grant of the Brain and Cognition programme of the University Utrecht.

Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is hosted on the Dutch National e-Infrastructure with the support of SURF Cooperative and financial support by the Netherlands Scientific Organization (NWO 480-05-003 PI: Posthuma).


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics

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

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Journal Title:

Nature Communications


Volume 7


, Pages 10967-10967

Type of Work:

Article | Final Publisher PDF


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.

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© 2016, Rights Managed by Nature Publishing Group

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).

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