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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 x 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.
