Genes identified outside of GWAS have also produced promising insights. Work pioneered by Binder, Ressler, and colleagues has linked variation in FKBP5 to pleiotropic stress-related health effects (e.g., PTSD, depression, Alzheimer’s disease, and aging) and related biological correlates (e.g., cortisol response, amygdala function) (Zannas et al., 2016). FKBP5 is a critical regulator of the hypothalamic-pituitary-adrenal (HPA) axis; it is a co-chaperone of the glucocorticoid receptor (GR) complex that diminishes GR sensitivity to cortisol resulting in an impaired ability of the HPA axis to return to homeostasis and transcriptionally regulate the genome. Through a series of programmatic experiments, Klengel and colleagues (Klengel et al., 2013) have shown that increased GR-stimulated FKBP5 expression observed among individuals with at least one T allele at rs1360780 may arise from alterations in the 3D structure of FKBP5. The T allele brings a long range enhancer 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
