FKBP5 splice variant alterations in the human cortex of psychiatric disorders

Exposure to high levels of adversity, such as maltreatment or geopolitical conflict, is a robust risk factor for severe psychiatric illness and is often associated with reduced treatment efficacy. The glucocorticoid receptor co-chaperone FK506 Binding Protein 51 (FKBP51), encoded by FKBP5 (chromosome 6p21.31), is a key regulator of the cortisol-induced stress response and a potential therapeutic target for stress-related psychiatric disorders. FKBP5 induction is moderated by a complex interplay of clinically relevant features including age and genotype, however, little is known about the role of mRNA splicing and the resulting protein isoforms in the human brain. Here, we characterise the expression profiles of three minor FKBP5 transcript variants (variants 2-4) in a large cohort of postmortem human brain samples from the dorsolateral prefrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia/major depressive disorder/bipolar disorder; n = 329) and controls (n = 231). Overall, expression of variant 3 (encoding full-length FKBP51) and variant 4 (encoding truncated FKBP51) showed the same neurotypical ageing trajectory as variant 1, while the lowly expressed variant 2 (encoding full-length FKBP51) showed no association with ageing past adolescence. In individuals with schizophrenia and major depressive disorder, we found increased expression of the same variants which may be partly moderated by genotype, given rs1360780 risk allele carriers had increased abundance of variants 3 and 4, but not variant 2. These findings suggest that in the human dorsolateral prefrontal cortex, minor FKBP5 mRNA splice variants follow a similar pattern of expression as the predominant variant 1.