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, W.H.J. Meeus, Susan Branje, Christine M. Heim, Charles B. Nemeroff, Jonathan Mill, Leonard C. Schalkwyk, Menno P. Creyghton, Rene S. Kahn, Marian Joels, Elisabeth B. Binder, Marco P. M. Boks

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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 languageEnglish
Article number10967
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 2016

Cite this

Houtepen, L. C., Vinkers, C. H., Carrillo-Roa, T., Hiemstra, M., van Lier, P. A., Meeus, W. H. J., ... Boks, M. P. M. (2016). Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. Nature Communications, 7, [10967]. https://doi.org/10.1038/ncomms10967
Houtepen, Lotte C. ; Vinkers, Christiaan H. ; Carrillo-Roa, Tania ; Hiemstra, Marieke ; van Lier, Pol A. ; Meeus, W.H.J. ; Branje, Susan ; Heim, Christine M. ; Nemeroff, Charles B. ; Mill, Jonathan ; Schalkwyk, Leonard C. ; Creyghton, Menno P. ; Kahn, Rene S. ; Joels, Marian ; Binder, Elisabeth B. ; Boks, Marco P. M. / Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. In: Nature Communications. 2016 ; Vol. 7.
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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.",
author = "Houtepen, {Lotte C.} and Vinkers, {Christiaan H.} and Tania Carrillo-Roa and Marieke Hiemstra and {van Lier}, {Pol A.} and W.H.J. 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, {Rene S.} and Marian Joels and Binder, {Elisabeth B.} and Boks, {Marco P. M.}",
year = "2016",
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Houtepen, LC, Vinkers, CH, Carrillo-Roa, T, Hiemstra, M, van Lier, PA, Meeus, WHJ, Branje, S, Heim, CM, Nemeroff, CB, Mill, J, Schalkwyk, LC, Creyghton, MP, Kahn, RS, Joels, 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

Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans. / Houtepen, Lotte C.; Vinkers, Christiaan H.; Carrillo-Roa, Tania; Hiemstra, Marieke; van Lier, Pol A.; Meeus, W.H.J.; Branje, Susan; Heim, Christine M.; Nemeroff, Charles B.; Mill, Jonathan; Schalkwyk, Leonard C.; Creyghton, Menno P.; Kahn, Rene S.; Joels, Marian; Binder, Elisabeth B.; Boks, Marco P. M.

In: Nature Communications, Vol. 7, 10967, 2016.

Research output: Contribution to journalArticleScientificpeer-review

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, W.H.J.

AU - Branje, Susan

AU - Heim, Christine M.

AU - Nemeroff, Charles B.

AU - Mill, Jonathan

AU - Schalkwyk, Leonard C.

AU - Creyghton, Menno P.

AU - Kahn, Rene S.

AU - Joels, Marian

AU - Binder, Elisabeth B.

AU - Boks, Marco P. M.

PY - 2016

Y1 - 2016

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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DO - 10.1038/ncomms10967

M3 - Article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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ER -