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Primary open-angle glaucoma (POAG) can develop even within normal ranges of intraocular pressure, and this type of glaucoma (so-called ‘normal-tension glaucoma [NTG]’) is highly prevalent in East Asia including Korea and Japan. We conducted exome chip analysis to identify low-frequency and rare variants associated with POAG from the primary cohort (309 POAG patients and 5,400 control, all Koreans). For replication, Korean (310 POAG patients and 5,612 controls) and Japanese (565 POAG patients and 1,104 controls) cohorts were further investigated by targeted genotyping. SNP rs116121322 in  LRRC27  showed nominally significant association with POAG in the discovery cohort (OR = 29.85,  P  = 2E–06). This SNP was validated in the Korean replication cohort but only in the NTG subgroups (OR = 9.86,  P  = 0.007). Japanese replication cohort did not show significant association with POAG ( P  .00.44). However, the meta-analysis in the entire cohort revealed significant association of rs116121322 with POAG (OR combined  = 10.28,  P  combined  = 1.4E–07). The LRRC27 protein expression was confirmed from human trabecular meshwork cells. For gene-based testing,  METTL20  showed a significant association in POAG ( P  combined  = 0.002) and in the subgroup of NTG ( P  combined  = 0.02), whereas  ZNF677  were significantly associated with only in the subgroup of high-tension glaucoma ( P  combined  = 1.5E–06). Our findings may provide further genetic backgrounds into the pathogenesis of POAG, especially for the patients who have lower baseline intraocular pressures.

Exploring the Novel Susceptibility Gene Variants for Primary Open-Angle Glaucoma in East Asian Cohorts: The GLAU-GENDISK Study