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Abstract The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (P combined = 4.3 × 10−5, OR = 0.72, I2 = 0). Additionally, we replicated the association of one known SNP, rs33912345 (P combined = 0.0061, OR = 0.69, I2 = 45%), with POAG in the Chinese cohorts but not in the Japanese cohort (P > 0.6). Another known SNP, rs10483727, was nominally associated with POAG in the two Chinese cohorts (P combined = 0.017, OR = 0.70, I2 = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (P combined <0.005). Furthermore, two haplotypes, C-C (P combined = 1.13 × 10−5, OR = 1.41, I2 = 0) and A-A (P combined = 0.045, OR = 0.68, I2 = 70%), defined by rs33912345-rs12436579 were associated with POAG in Chinese but not in Japanese. In conclusion, this study confirmed the association between two GWAS SNPs in SIX6 (rs33912345 and rs10483727) and POAG. Also, a SNP, rs12436579, not associated with POAG before, was found to be associated with POAG in Chinese. Further studies are warranted to elucidate the role of this novel SNP in POAG. Highlights • Validation of reported association between the SIX6 SNPs and POAG. • Identification of a novel SNP rs12436579 associated with POAG in Southern Chinese. • Haplotype rs33912345-rs12436579 had a stronger association than single SNP. • Different association patterns of SIX6 with POAG between Chinese and Japanese. [ABSTRACT FROM AUTHOR]