BACKGROUND: Primary open-angle glaucoma (POAG) is a subtype of glaucoma that accounts for 60%~70% of all cases. Its pathogenic mechanism is intricate and its pathogenic process is concealed. Numerous significant biological processes associated with POAG continue to be elucidated. METHODS: In this study, by exploring the expression data of POAG tissues and normal tissues, we mined the regulatory lncRNAs and mRNAs closely associated with the pathogenesis and progression of POAG by exploring a regulatory network of competing endogenous RNA (ceRNA), established by integrating gene expression data with the known lncRNA-miRNA and miRNA-mRNA-regulatory interactions. The key regulatory pathways and regulatory elements of POAG were identified by topological analysis. Simultaneously, the exome data of 28 cases with POAG and healthy controls were analyzed to identify high-frequency mutations and genes. RESULTS: A total of 2712 differentially expressed genes were identified, including 1828 mRNAs and 884 lncRNAs. Network analysis suggested that lncRNAs such as HAGLR, HOTAIR and MIR29B2CHG, and mRNAs such as PPP6R3, BMPR2 and CFL2, may be involved in the onset and progression of POAG. In addition, 55 mutations with potential pathogenicity were identified. CONCLUSION: These genes and mutations provide novel potential genetic heterogeneity and genetic susceptibility of POAG, as well as fresh suggestions for elucidating the molecular mechanism underlying the pathogenesis of POAG.