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

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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
Number of pages10
JournalNature Communications
Issue number3
Publication statusPublished - 21 Mar 2016


  • Biological sciences
  • Genetics
  • Molecular biology
  • Neuroscience

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