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.
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Lotte C
authors.initials: LC
authors.lastname: Houtepen
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Christiaan H
authors.initials: CH
authors.lastname: Vinkers
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Carrillo-Roa
authors.affiliation: Research Centre Adolescent Development, Department Youth &Family, University Utrecht (UU), Utrecht 3584 CS, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Hiemstra
authors.affiliation: Department of Developmental Psychology, VU University, Amsterdam 1081 BT, The Netherlands.
authors.forename: Pol A
authors.initials: PA
authors.lastname: van Lier
authors.affiliation: Research Centre Adolescent Development, Department Youth &Family, University Utrecht (UU), Utrecht 3584 CS, The Netherlands.|Department of Developmental Psychology, Tilburg University 5000 LE, Tilburg, The Netherlands.
authors.forename: Wim
authors.initials: W
authors.lastname: Meeus
authors.affiliation: Research Centre Adolescent Development, Department Youth &Family, University Utrecht (UU), Utrecht 3584 CS, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: Branje
authors.affiliation: Institute of Medical Psychology, Charité-University Medicine, Medical Centre, 10117 Berlin, Germany.|Department of Biobehavioral Health, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Heim
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Leonard M. Miller School of Medicine, University of Miami, Miami, 33136, Florida, USA.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.affiliation: University of Exeter Medical School, University of Exeter, EX2 5DW, Devon, UK.|Institute of Psychiatry, Psychology &Neuroscience, King's College London, SE5 8AF, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.affiliation: School of Biological Sciences, University of Essex, CO4 3SQ Colchester, UK.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht (UMCU), Utrecht 3584CT, The Netherlands.
authors.forename: Menno P
authors.initials: MP
authors.lastname: Creyghton
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: René S
authors.initials: RS
authors.lastname: Kahn
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht (UMCU), Utrecht 3584 CG, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Joëls
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.|Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
authors.forename: Marco P M
authors.initials: MP
authors.lastname: Boks
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002648:Child; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005006:Ethnicity / Q000235:genetics; D005260:Female; D053263:Gene Regulatory Networks; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D019089:Stem Cell Factor / Q000235:genetics; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics*; D014947:Wounds and Injuries / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: D006657:Histones; D019089:Stem Cell Factor; D006854:Hydrocortisone