Large‐scale Whole‐Exome Sequencing Defines the Protein‐Coding Architecture of Retinal Structure, Visual Function, and Major Blinding Diseases

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.

Authors

Institutions

Publication Details

Journal
Advanced Science
Published
2026-07-24
DOI
https://doi.org/10.1002/advs.76582
Primary Topic
Retinal Development and Disorders
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Large‐scale Whole‐Exome Sequencing Defines the Protein‐Coding Architecture of Retinal Structure, Visual Function, and Major Blinding Diseases

Mengxi Shen, J K Chen, Qiyu Bo, T B Zhang et al.
Advanced Science
Retinal Development and Disorders
article

Large‐scale Whole‐Exome Sequencing Defines the Protein‐Coding Architecture of Retinal Structure, Visual Function, and Major Blinding Diseases

Mengxi Shen, J K Chen, Qiyu Bo, T B Zhang, T Li, Chenyue Hang, Shunxiang Gao, Wei Cheng, Mao Ym, Jingxiao Du, Bai Lu, Tianyuan Zhao, Yazhi Wang, Xiaoling Wan, Bang‐Sheng Wu, Jie Yu, Yutian Jiao, J Sun, L Yang, Yang Dou, Yijun Ge, Jianqing Li, Xiaodong Sun, Huixun Jia
article en

Abstract

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.

Advanced Science
Shanghai Academy of Social Sciences (CN), McGovern Institute for Brain Research (US), University of Miami (US), Shanghai Jiao Tong University (CN), Fudan University (CN), Soochow University (CN), Shanghai Genon Biological Products (China) (CN), Chinese Institute for Brain Research (CN), Shanghai First People's Hospital (CN), Shanghai Agrobiological Gene Center (CN), Center for High Pressure Science & Technology Advanced Research (CN), Shanghai Academy of Environmental Sciences (CN), First Affiliated Hospital of Soochow University (CN), Huashan Hospital (CN), Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
Changping Laboratory, Natural Science Foundation of Shanghai, Ministry of Science and Technology, National Natural Science Foundation of China, Shanghai Municipal Education Commission, Science and Technology Commission of Shanghai Municipality
Openalex Percentile: Top 14%
Retinal Development and Disorders
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.