First report of RNA editing in human retina – a process central to photoreceptor health, and a risk factor for both AMD and rarer macular degeneration

Abstract

Purpose : 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.

Methods : We quantified RNA editing sites across the transcriptomes of >500 donor retinae, calculated differentially edited sites in AMD (N=346) vs control (N=105) retinae, and used donor-matched genotypes to reveal ~10,000 '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, macular telangiectasia II and glaucoma. Results at shiny.wehi.edu.au/ansell.b/retina_rnaed_browser/

Results : 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. Some 300 differentially edited sites that are risk factors for AMD pathogenesis, and ~10,000 sites in 2,765 genes are under genetic control ('edQTLs'). 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 II and glaucoma genetic risk factors respectively.

Conclusions : RNA editing is an under-studied but ubiquitous and functionally important process in the human retina which both represents an attractive alternative to DNA-based gene therapy, and mediates part of the genetic risk of major sight-threatening diseases.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.