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

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173 Scopus citations

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 (US)
Article number	10967
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10967
State	Published - Mar 21 2016

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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, 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.",

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, 10967. https://doi.org/10.1038/ncomms10967

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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.

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

Abstract

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