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

• DOI: 10.1038/ncomms10967
• Publication Date: 2016-03-21T10:07:21Z
• Authors: Lotte C. Houtepen; Christiaan H. Vin...; 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
• Keywords: Adult; Male; 0301 basic medicine; Adolescent; Hydrocortisone; Molecular biology; QH301 Biology; Science; 610; 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit; Article; Epigenesis, Genetic; Histones; 03 medical and health sciences; Research Support, N.I.H., Extramural; Journal Article; Ethnicity; Genetics; Humans; Gene Regulatory Networks; SDG 14 - Life Below Water; Child; Aged; Stem Cell Factor; 0303 health sciences; Models, Genetic; Genome, Human; Research Support, Non-U.S. Gov't; Q; Age Factors; 600; DNA Methylation; Middle Aged; Wessex Classification Subject Headings::Oncology. Pathology.::Genetics; Biological sciences; Genetic Loci; FOS: Biological sciences; Female; RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry; Genome-Wide Association Study; Neuroscience

AbstractDNA 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.