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

• Authors: Lotte C. Houtepen, University Medical Center Utrecht; Christiaan H. Vinkers, University Medical Center Utrecht; Tania Carrillo-Roa, Max Planck Institute of Psychiatry; Marieke Hiemstra, University of Utrecht; Pol A. van Lier, Vrije Universiteit Amsterdam; Wim Meeus, University of Utrecht; Susan Branje, University of Utrecht; Christine M. Heim, Charité-University Medicine; Charles B. Nemeroff, University of Miami; Jonathan Mill, University of Exeter; Leonard C Schalkwyk, University of Essex; Menno P. Creyghton, Hubrecht Institute; René S. Kahn, University Medical Center Utrecht; Marian Joëls, University Medical Center Utrecht; Elisabeth Binder, Emory University; Marco P.M. Boks, University Medical Center Utrecht
• Journal Title: Nature Communications
• Volume: Volume 7
• Publisher: Nature Publishing Group: Nature Communications | 2016-03-01, Pages 10967-10967
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/ncomms10967
• Subjects: Biology, Neuroscience; Biology, Genetics; Psychology, Developmental
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; PUBLIC SPEAKING TASK; RECEPTOR GENE NR3C1; GLUCOCORTICOID-RECEPTOR; EPIGENETIC REGULATION; HUMAN BRAIN; RESPONSES; DEPRESSION; MICROARRAY; EXPRESSION; NEUROENDOCRINE

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.