Dangdang Wang,1,2,* Yanyu Pu,1,2,* Xi Gao,1,2 Lihong Zeng,1,2 Hong Li1,2 

1Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory for the Prevention and Treatment of Major Blinding Eye Diseases, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Hong Li, Department of Ophthalmology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China, Email lihong@hospital.cqmu.edu.cn

Purpose: Genome-wide association studies (GWAS) have identified multiple genetic loci associated with primary open-angle glaucoma (POAG). However, the mechanisms by which these loci contribute to POAG progression remain unclear. This study aimed to identify potential causative genes involved in the development of POAG.
Methods: We utilized multi-dimensional high-throughput data, integrating proteome-wide association study(PWAS), transcriptome-wide association study (TWAS), and summary data-based Mendelian randomization (SMR) analysis. This approach enabled the identification of genes influencing POAG risk by affecting gene expression and protein concentrations in the bloodstream. The key gene was validated through enzyme-linked immunosorbent assay (ELISA) analysis.
Results: PWAS identified 86 genes associated with altered blood protein levels in POAG patients. Of these, eight genes (SFTPD, CSK, COL18A1, TCN2, GZMK, RAB2A, TEK, and GNLY) were identified as likely causative for POAG (PSMR <  0.05). TWAS revealed that GNLY was significantly associated with POAG at the gene expression level. GNLY-interacting genes were found to play roles in immune dysregulation, inflammation, and apoptosis. Clinical and cell-based validation confirmed reduced GNLY expression in POAG groups.
Conclusion: This study reveals GNLY as a significant potential therapeutic target for managing primary open-angle glaucoma.

Keywords: primary open-angle glaucoma, GNLY, PWAS, TWAS