region in intron 2 into physical contact with the transcription start site (TSS) thereby allowing it to affect expression. Effects of these conformation changes can be further compounded by T-allele specific childhood stress-related demethylation of a functional glucocorticoid response element within intron 7, which also contacts the TSS. Demethylation here, which some evidence suggests may only be stable following stress exposure early in life, enhances FKBP5 expression in the context of GR stimulation, resulting in a further reduction of HPA axis negative feedback. It is thus possible that the 3D conformation changes lead to a prolonged stress response that, when coupled with early life stress exposure, results in lasting epigenetic changes further impairing HPA axis regulation including its ability to influence the transcriptome. While recent large-scale GWAS of stress-related disorders (e.g., PTSD and depression) have not identified variants in FKBP5 (Duncan et al., 2017, Stein et al., 2016, Wray and Sullivan, 2017), this is unsurprising given the highly interactional nature of these molecular mechanisms and trauma exposure during early life (i.e., without GWASxE such effects would not be expected).
