Brain and cognitive correlates of FKBP5: methylation patterns in schizophrenia

Schizophrenia (SZ) is a neurodevelopmental disorder influenced by genetic and environmental factors. The stress-related gene FKBP5 shows genetic, epigenetic, and expression variability associated with SZ. Although FKBP5 methylation has been related to brain structural changes in psychiatric conditions, its role in the cortical thinning and cognitive deficits distinctive of SZ remains unexplored. We examined whether case-control differences in FKBP5 methylation are associated with cortical thickness and cognitive performance. In a case-control study (35 SZ, 35 HC), we assessed FKBP5 methylation (EpiTYPER), cortical thickness (FreeSurfer), and intelligence quotient (IQ). A sparse PLS-DA approach identified a latent component (LC1) capturing methylation differences. We tested the effect of LC1 on cortical thickness (brain clusters showing group differences) and IQ scores, using linear regressions. Next, we examined the relationship among methylation, neuroanatomical, and cognitive changes through a mediation analysis. LC1 was associated with reduced cortical thickness in the right pars opercularis (β = -2.15, p = 0.002). Thickness in this region was positively associated with IQ (β = 35.14, p = 0.011), but there was no direct LC1-IQ association. Mediation analysis revealed a significant indirect effect of methylation on IQ via cortical thickness (ACME = -62.96, p = 0.046; ~40% of the total effect), which was not significant after adjusting for diagnosis. Our results represent the first analysis of the effect of FKBP5 methylation on neuroanatomical and cognitive variability in SZ, highlighting that methylation-related differences associated with the disorder are connected to structural and cognitive alterations.