Multi-omics of retinas from free-ranging primates with naturally occurring thin retinal nerve fiber layer

Abstract

Purpose : The interaction of environmental and genetic elements is implicated in glaucoma, but elucidating the important risk factors is difficult due to poor understanding of associations between clinical and molecular features. Our purpose is to determine tissue-level multi-omic associations with naturally occurring thin retinal nerve fiber layer (RNFL), a commonly used indicator of glaucomatous phenotype, in a population of free-ranging primates living in a naturalistic environment.

Methods : We studied clinical and ‘omic profiles of free-ranging adult rhesus macaques removed from the Cayo Santiago colony for population management. From 89 animals, we selected 18 (9M and 9F) with thin RNFLs (65.3-81.4 mm) and 18 (9M, 9F) with average (84.6 – 103.2 mm) RNFLs, assessed by OCT under anaesthetic. We were provided with eye tissues from the same animals and generated total RNA transcriptomes from retinal biopsies and untargeted global aqueous metabolomic profiles using the remaining retinal tissues. DESEQ2 was used to identify differentially expressed genes, which were piped into the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to discover related pathways. The integration of gene expression and metabolomic data were conducted using mixomic.

Results : 14 genes were differentially expressed in animals with thin versus average RNFL thickness. Among these, SFRP2, which is important for retinal development and myogenesis, and MIR7173, which affects the stability and translation of mRNAs, were among the most strongly differentially expressed. KEGG analysis highlighted 17 pathways that were enriched, including those linked with type I diabetes and cellular senescence. Considering metabolites, individuals with thin RNFLs had relatively less sorbitol and a higher abundance of six metabolites, including carnosine, methylmalonate, and retinal. Heatmaps of transcriptomic versus metabolomic profiles revealed a greater number of multiomic correlations, especially positive correlations, among eyes with thinner RNFLs.

Conclusions : The ‘omic profiles and multiomic interactions differ between free-ranging macaques with thin vs average RNFLs. These data improve our understanding of the biology of glaucomatous phenotypes and may help reveal the pathophysiology of glaucoma.

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

 

Mixomic heatmaps and gene-metabolite interactions are different between primates with thin versus average RNFL thickness