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

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 Schalkwyk; Menno P Creyghton; René S Kahn; Marian Joëls; Elisabeth B Binder; Marco P M Boks

doi:10.1038/ncomms10967

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

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 Schalkwyk, Menno P Creyghton, René S Kahn, Marian Joëls, Elisabeth B Binder, Marco P M Boks

Bristol Medical School (PHS)

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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.

Original language	English
Article number	10967
Number of pages	10
Journal	Nature Communications
Volume	7
Issue number	3
DOIs	https://doi.org/10.1038/ncomms10967
Publication status	Published - 21 Mar 2016

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SDG 3 Good Health and Well-being

Keywords

Biological sciences
Genetics
Molecular biology
Neuroscience

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This is the final published version of the article (version of record). It first appeared online via Nature at http://www.nature.com/ncomms/2016/160321/ncomms10967/full/ncomms10967.html. Please refer to any applicable terms of use of the publisher.
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Houtepen, L. C., Vinkers, C. H., Carrillo-Roa, T., Hiemstra, M., van Lier, P. A., Meeus, W., Branje, S., Heim, C. M., Nemeroff, C. B., Mill, J., Schalkwyk, L. C., Creyghton, M. P., Kahn, R. S., Joëls, M., Binder, E. B., & Boks, M. P. M. (2016). Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nature Communications, 7(3), Article 10967. https://doi.org/10.1038/ncomms10967

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

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.",

keywords = "Biological sciences, Genetics, Molecular biology, Neuroscience",

author = "Houtepen, \{Lotte C\} and Vinkers, \{Christiaan H\} and Tania Carrillo-Roa and Marieke Hiemstra and \{van Lier\}, \{Pol A\} and Wim Meeus and Susan Branje and Heim, \{Christine M\} and Nemeroff, \{Charles B\} and Jonathan Mill and Schalkwyk, \{Leonard C\} and Creyghton, \{Menno P\} and Kahn, \{Ren{\'e} S\} and Marian Jo{\"e}ls and Binder, \{Elisabeth B\} and Boks, \{Marco P M\}",

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doi = "10.1038/ncomms10967",

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Houtepen, LC, Vinkers, CH, Carrillo-Roa, T, Hiemstra, M, van Lier, PA, Meeus, W, Branje, S, Heim, CM, Nemeroff, CB, Mill, J, Schalkwyk, LC, Creyghton, MP, Kahn, RS, Joëls, M, Binder, EB & Boks, MPM 2016, 'Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans', Nature Communications, vol. 7, no. 3, 10967. https://doi.org/10.1038/ncomms10967

TY - JOUR

T1 - Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

AU - Houtepen, Lotte C

AU - Vinkers, Christiaan H

AU - Carrillo-Roa, Tania

AU - Hiemstra, Marieke

AU - van Lier, Pol A

AU - Meeus, Wim

AU - Branje, Susan

AU - Heim, Christine M

AU - Nemeroff, Charles B

AU - Mill, Jonathan

AU - Schalkwyk, Leonard C

AU - Creyghton, Menno P

AU - Kahn, René S

AU - Joëls, Marian

AU - Binder, Elisabeth B

AU - Boks, Marco P M

PY - 2016/3/21

Y1 - 2016/3/21

N2 - 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.

AB - 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.

KW - Biological sciences

KW - Genetics

KW - Molecular biology

KW - Neuroscience

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DO - 10.1038/ncomms10967

M3 - Article (Academic Journal)

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SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

IS - 3

M1 - 10967

ER -

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

Abstract

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