Conversion 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. Editing can change the protein sequence, and dampen the innate immune response. This has been extensively documented in the brain and other body tissues, revealing tissue-specific and genetically-determined landscapes of modifications that contribute to multiple diseases. However, despite the importance of RNA editing in the CNS, nothing is known about this process in the human retina.
We quantified RNA editing sites across the transcriptomes of >500 donor retinae, calculated differentially edited sites in age-related macular degeneration (‘AMD’ ; N=346) vs control (N=105) retinae at two tissue locations (macula and periphery), and used donor-matched genotypes to reveal ~2,000 'editing QTLs.' Clustering and colocalization analyses were used to compare the RNA editome of the retina with 50 other body tissues, and to identify editing sites that mediate the genetic risk of AMD, a rarer macular disease 'macular telangiectasia II', and glaucoma.
We found 80% of editing sites occurred within intronic Alu repeats, and 3’ UTR sequence in protein-coding RNAs. Functionally essential editing-based amino acid substitutions reported in brain are also highly prevalent in retina. Enrichment analysis revealed the hypoxia factor HIF3a to be among 27 hyper-edited genes, and synaptic vesicle recycling genes to be protected from editing. We found 25% of sites restricted to the retina, and within genes strongly enriched for photoreceptor cell functions. There was little overlap (~15%) between retinal edQTLs and eQTLs, however strong agreement was found between retinal edQTLs and 30 other tissues, most notably brain. Colocalization analysis revealed several loci where genetically-mediated RNA editing differences may drive AMD, MacTel, and glaucoma genetic risk factors respectively.