Large-scale Whole-Exome Sequencing Defines the Protein-Coding Architecture of Retinal Structure, Visual Function, and...

The retina is an accessible extension of the central nervous system, yet the protein-coding architecture linking retinal structure, visual function, and major blinding diseases remains poorly defined. Here, using large-scale whole-exome sequencing data from 356,982 UK Biobank participants, exome-wide gene-based tests of rare coding variants and single-variant analyses of common coding variants are performed. A total of 22 significant rare-variant gene-based associations involving 16 genes are identified, including 12 novel genes, 10 of which are independently supported in the All of Us cohort (N = 245,388). Single-variant analyses identify 243 independent common coding variants in 126 genes, including 24 novel genes. CFI, C3, and RIOX1 show associations across retinal structure, visual function, and disease phenotypes, supporting cross-domain pleiotropy. Among the disease-associated genes, the novel gene FYB2 is prioritized for experimental validation, supported by retinal pigment epithelium (RPE)-related expression evidence and clinical relevance in Cox analyses. FYB2 knockdown aggravates barrier dysfunction in human induced RPE (iRPE) cells, supporting a potential role in diabetic retinopathy. These findings define the protein-coding architecture of retinal phenotypes, and support shared genetic links across retinal structure, visual function, and disease. The identified genes provide candidate targets for mechanistic investigation in blinding retinal disorders.