Primary open-angle glaucoma (POAG), known as a common ocular disease with genetic heterogeneity, is characterized by progressive optic disc atrophy and visual field defects. This study aimed to assess the contribution of previously reported POAG-associated genes and investigate potential functional variations and genotype-phenotype correlations in a Han Chinese population. DNA from 500 cases and 500 controls was pooled and sequenced using a customized panel of 398 candidate genes. After prioritization, 21 SNPs from 16 genes were genotyped in the first replication cohort (500 cases and 500 controls), and 9 SNPs were genotyped in the second replication cohort (500 cases and 500 controls). Allelic associations and odds ratios were adjusted for age and sex, while linear regression assessed SNP correlations with POAG endophenotypes. Haplotype analysis and linkage disequilibrium were performed using Haploview. In silico prediction tools were used to predict pathogenicity and function. SNPs from MFN2, DGKG, PKHD1, PTPRJ, and LTBP2 were associated with POAG in at least one cohort, and SNPs from EXOC2, PTPRJ, and LTBP2 showed significant correlations with intraocular pressure. Additionally, haplotype analysis revealed a significant association between the EXOC2 TGC haplotype and POAG risk. We validated several candidate genes and identified novel SNPs, providing further insight into the genetic architecture of POAG in the Han Chinese population.