Lower cortical FKBP5 DNA methylation at key enhancer sites is associated with older age and higher gene expression in schizophrenia

An increasingly compelling body of literature indicates the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51) is a promising target for novel psychiatric therapeutics. However, the mechanisms regulating the corresponding FKBP5 gene directly in the human brain remain largely unknown yet are needed to facilitate the development of precise mechanism-based treatment approaches. Here, we examined FKBP5 DNA methylation patterns in postmortem human brain samples from the dorsolateral prefrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia, major depression, or bipolar disorder; n=329) and controls n=231. We identified that cytosine-phosphate-guanine-dinucleotide (CpG) specific FKBP5 DNA methylation is altered in psychiatric disorders across the FKBP5 locus, and that these changes are differentially associated with age and genotype (rs1360780 CC vs CT/TT). Individuals with schizophrenia had significantly lower levels of DNA methylation in the proximal enhancer of FKBP5, which also negatively correlated with FKBP5 gene expression. These changes were also associated with predicted glucocorticoid response elements (GREs) in the proximal enhancer, but not other transcription factor binding sites. This evidence supports that in the human cortex, FKBP5 DNA methylation is associated with both genetic and ageing effects, and that the associations between these factors vary at a diagnosis-specific level in psychopathology. This may have implications for developing FKBP5-targeted therapeutics and defining a subgroup of patients who will benefit from such treatments.