CircRNA hypomethylation in the human amygdala implicates FKBP5 in alcohol use disorder

Genome- and phenome-wide association studies implicate the RNA demethylase FTO in alcohol use disorder (AUD), yet the RNA methylation landscape in AUD remains poorly characterized. Analyzing postmortem human basolateral amygdala (BLA) tissue, a key brain region in AUD-related behaviors, we found extensive m⁶A hypomethylation uniquely affecting circular RNAs (circRNAs). Notably, FKBP5-hosted circRNAs (circFKBP5s) exhibited pronounced hypomethylation correlating with elevated expression of FKBP5 mRNA isoforms. These findings were replicated in an animal model of alcohol dependence. Predictive analyses suggest that circFKBP5s influence genes involved in neurodevelopmental processes and neuronal identity. These findings uncover a novel aspect of AUD neurobiology linked to circRNA methylation.