Global landscape and genetic regulation of RNA editing in cortical samples from individuals with schizophrenia

RNA editing critically regulates neurodevelopment and normal neuronal function. We surveyed RNA editing across 364 schizophrenia cases and 383 control postmortem brain samples from the CommonMind Consortium, comprising two regions: dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex. In schizophrenia, RNA editing sites in genes encoding AMPA-type glutamate receptors and post-synaptic density proteins were less edited, while those encoding translation initiation machinery were more edited. These sites replicate between brain regions, map to 3’UTR and intronic regions, share common sequence motifs, and map to binding sites for RNA binding proteins crucial for neurodevelopment. These findings cross-validate in hundreds of non-overlapping DLPFC samples. Furthermore, ~30% of RNA editing sites associate with cis-regulatory variants (edQTLs). Fine-mapping edQTLs with schizophrenia GWAS loci revealed co-localization of 11 edQTLs with 6 GWAS loci. Our findings demonstrate widespread altered RNA editing in schizophrenia and its genetic regulation, and suggest RNA editing mechanisms of schizophrenia neuropathology.