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

OBJECTIVE: 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: 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: 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: mRNA levels may be mediated by these epigenetic mechanisms.