Common variants on chromosome 9p21 are associated with normal tension glaucoma

Abstract

Although intraocular pressure (IOP) is the most definitive cause of glaucoma, a subtype of open angle glaucoma (OAG) termed normal tension glaucoma (NTG), which occurs in spite of normal IOP, accounts for a large part of glaucoma cases, especially in Japan. To find common genetic variants contributing to NTG in Japanese patients, we conducted a genome-wide association study (GWAS). We performed the first screening for 531,009 autosomal SNPs with a discovery cohort of 286 cases and 557 controls, and then a second screening for the top 30 suggestive loci in an independent cohort of 183 cases and 514 controls. Our findings identified a significantly associated SNP; rs523096 [combined p-value = 7.40× 10(-8), odds ratio (OR)= 2.00 with 95% confidence interval (CI) 1.55-2.58] located 10 kbp upstream of CDKN2B on chromosome 9p21. Moreover, analysis of another independent case-control set successfully replicated the results of the screening studies (combined values of all 3 stages p = 4.96 × 10(-11), OR= 2.13 with 95% CI 1.69-2.68). The SNPs near rs523096 were recently reported to be associated with OAG associated with elevated IOP in primary open-angle glaucoma (POAG), the predominant subtype of glaucoma in Caucasian populations. Our results revealed that the 9p21 locus is also associated with NTG in Japanese. In addition, we identified SNPs more strongly associated with NTG.

Figure 1. Manhattan plots of genome-wide association study for NTG.

Negative common logarithm of p-value plots for genome-wide association study in the first screening. The X-axis indicates chromosomes and their positions, and the Y-axis indicates the negative common logarithm of the association p-value of 531,009 SNPs. No SNP showed a genome-wide significance at p = 9.416 × 10⁻⁸ (Bonferroni’s correction).

Figure 2. LD plots on 9p21 in first screening data in dense association mapping region.

Upper panel shows plots of negative common logarithm of association p-values for 9p21 locus. Each dot represents an SNP from the first screening and the colors of the dots represent the extent of linkage disequilibrium with rs523096 (purple diamond). Shaded area in the middle panel of the gene structures indicates the 87-kbp region, defined as the dense association mapping region. Lower panel shows an LD plot (D-prime) of Japanese specimens from HapMap III data.