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

Pre-Amsterdam UMC

Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Utrecht University, Netherlands
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Research Centre Adolescent Development, Department Youth &Family, University Utrecht (UU), Utrecht 3584 CS, The Netherlands.
Department of Developmental Psychology, VU University, Amsterdam 1081 BT, The Netherlands.
Department of Developmental Psychology, Tilburg University 5000 LE, Tilburg, The Netherlands.
Department of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802, USA.
Department of Psychiatry and Behavioral Sciences, Leonard M. Miller School of Medicine, University of Miami, Miami, 33136, Florida, USA.
Medical Research Council-Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom; [email protected] [email protected] [email protected].
School of Biological Sciences, University of Essex, CO4 3SQ Colchester, UK.
Hubrecht Institute-KNAW and University Medical Center Utrecht (UMCU), Utrecht 3584CT, The Netherlands.
Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30329, USA.

Research output: Contribution to journal › Article › Academic › peer-review

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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
Pages (from-to)	10967
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10967
Publication status	Published - 21 Mar 2016

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adolescent
Adult
Age Factors
Aged
Child
DNA Methylation/genetics
Epigenesis, Genetic
Ethnic Groups/genetics
Female
Gene Regulatory Networks
Genetic Loci
Genome, Human
Genome-Wide Association Study
Histones/metabolism
Humans
Hydrocortisone/metabolism
Male
Middle Aged
Models, Genetic
Stem Cell Factor/genetics
Stress, Psychological/blood
Wounds and Injuries/blood
Young Adult

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Genome-wide-dna-methylation-levels-and-altered-cortisol-stress-reactivity-following-childhood-trauma-in-humans.pdfFinal published version, 634 KBLicence: Taverne

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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, 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 = "Adolescent, Adult, Age Factors, Aged, Child, DNA Methylation/genetics, Epigenesis, Genetic, Ethnic Groups/genetics, Female, Gene Regulatory Networks, Genetic Loci, Genome, Human, Genome-Wide Association Study, Histones/metabolism, Humans, Hydrocortisone/metabolism, Male, Middle Aged, Models, Genetic, Stem Cell Factor/genetics, Stress, Psychological/blood, Wounds and Injuries/blood, Young Adult",

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\}",

year = "2016",

month = mar,

day = "21",

doi = "10.1038/ncomms10967",

language = "English",

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pages = "10967",

journal = "Nature communications",

issn = "2041-1723",

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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, pp. 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 - Adolescent

KW - Adult

KW - Age Factors

KW - Aged

KW - Child

KW - DNA Methylation/genetics

KW - Epigenesis, Genetic

KW - Ethnic Groups/genetics

KW - Female

KW - Gene Regulatory Networks

KW - Genetic Loci

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Histones/metabolism

KW - Humans

KW - Hydrocortisone/metabolism

KW - Male

KW - Middle Aged

KW - Models, Genetic

KW - Stem Cell Factor/genetics

KW - Stress, Psychological/blood

KW - Wounds and Injuries/blood

KW - Young Adult

U2 - 10.1038/ncomms10967

DO - 10.1038/ncomms10967

M3 - Article

SN - 2041-1723

VL - 7

SP - 10967

JO - Nature communications

JF - Nature communications

ER -

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

Abstract

UN SDGs

Keywords

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