Association Between Age-Dependent DNA Methylation Changes at FKBP5 Enhancer Sites and Increased Cortical Gene Expression in Schizophrenia.

OBJECTIVE: An increasingly compelling body of literature indicates that the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51; encoded by FKBP5) is a promising target for psychiatric therapeutics. Increased mRNA expression of FKBP5 in postmortem brains with psychiatric diagnoses and with aging have been reported previously. The epigenetic mechanisms underlying these effects in the human brain remain largely unknown. METHODS: The authors analyzed previously generated DNA methylation (DNAm) array, single-nucleotide polymorphism genotyping, and bulk RNA-, single-nucleus RNA-, and single-nucleus assay for transposase-accessible chromatin (snATAC)-sequencing data to examine FKBP5 DNAm patterns in postmortem human brain samples from the dorsolateral prefrontal cortex and orbitofrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia, major depressive disorder, or bipolar disorder) across two independent cohorts (N=378 cases and N=209 controls). RESULTS: Several cytosine-phosphate-guanine dinucleotides (CpGs) were identified across the proximal enhancer of the FKBP5 locus where DNAm was negatively correlated with gene expression, with validation across both cohorts. Data from single-nucleus analyses supported the relevance of these associations across all major cell types. In this functional region, as well as additional sites, associations were observed with age, rs1360780 genotype (CC versus CT/TT), and psychiatric diagnosis. Notably, individuals with schizophrenia exhibited significantly lower DNAm levels in the proximal enhancer region that showed additional converging effects of age and genotype, specifically in glucocorticoid response element-associated CpG sites. CONCLUSIONS: This evidence supports the association of aging and psychiatric diagnosis with changes in FKBP5 DNAm in functionally relevant regulatory elements of the human frontal cortex. This suggests that related changes in FKBP5 mRNA levels may be mediated by these epigenetic mechanisms.