Oral Presentation 44th Lorne Genome Conference 2023

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 (#35)

Brendan R E Ansell 1 2 , Roberto Bonelli 1 2 , Simon N Thomas 1 2 , Aravind Manda 1 2 , Rinki Ratnapriya 3 , Michele Pinelli 4 , Anand Swaroop 5 , Diego di Bernardo 4 , Sandro Banfi 4 , Melanie Bahlo 1 2
  1. Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Medical Biology, University of Melbourne, Parkville, VIC, Australia
  3. Baylor College of Medicine, Houston, Texas, USA
  4. Telethon Institute of Genetics & Medicine, Naples, Italy
  5. National Eye Institute - NIH, Bethesda, Maryland, USA

BACKGROUND: 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. RNA 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 & RESULTS: We present the first ever analysis of ~127,000 high-confidence RNA editing sites across the transcriptomes of >500 donor retinae. We found 80% of editing sites occurred within protein coding RNA, with the majority occurring in intronic Alu repeats, and 3’ UTR sequence. Important editing-based amino acid substitutions reported in brain are also highly prevalent in the 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 that 25% of sites are restricted to the retina, and within genes strongly enriched for photoreceptor cell functions. Differential editing between heathy (N=105) and AMD samples (346), revealed ~300 differentially edited sites that are potential risk factors for AMD pathogenesis. We identified editing QTLs (‘edQTLs’) in 391 donors, and found ~10,000 genetic loci impacting the editing frequency of 2,765 genes. There was little overlap (~15%) between edQTLs and eQTLs reported in the same cohort, however strong agreement was found between edQTLs in retina and 30 other tissues, most notably brain. To highlight the utility of our results to interpret GWAS signals, we performed colocalization of edQTLs with ocular GWAS disease risk loci. We identified six loci where genetically-mediated RNA editing differences may drive AMD, macular telangiectasia and glaucoma genetic risk factors respectively, suggesting a surprisingly prominent role for RNA editing in the health of the retina.