The retinal RNA editome is concentrated in photoreceptor-specific genes and genetically linked to vision loss

BACKGROUNDConversion of adenosine in RNA to inosine by ADAR enzymes, termed RNA editing, occurs at thousands of sites across the transcriptome, and is required for healthy development of the central nervous system. RNA editing can modify protein sequences, and dampen the innate immune response. RNA editing is tissue-specific and partly genetically determined. Modifications of RNA editing sites contribute to multiple diseases, particularly neurodevelopmental and neuropsychiatric diseases. Despite the importance of RNA editing in the brain, nothing is known about this process in the human retina. We describe the landscape of retinal editing revealing its importance in key biological processes that underpin vision. METHODS & RESULTSWe analysed the transcriptomes of >500 donor retinae and identified [~]153,000 high-confidence RNA editing sites. Some 80% of editing sites occurred within protein-coding RNA, with the majority in intronic Alu repeats, and 3 UTR sequence. Novel retina-specific sites were concentrated in genes related to photoreceptor function and which cause retinitis pigmentosa, most notably in PDE6A. Exonic, protein recoding sites were enriched in zinc-finger domains. AMD subjects exhibit relatively few differences in RNA editing compared to controls, consistent with limited gene expression differences. We identified [~]10,000 editing QTLs. The genetic architecture of editing in the retina resembles the brain, whereas editing and expression QTLs in the retina show modest genetic overlap. We report colocalization between edQTLs and retinal disease GWAS peaks for age-related macular degeneration, glaucoma and macular telangiectasia. These findings provide new insights into epi-transcriptomic regulation of genes critical for vision, and elaborate putative genetic disease driver mechanisms that appear to be independent of changes in gene expression.