Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma. Author Summary: Loss of vision from glaucoma, a common cause of blindness worldwide, is due to irreversible damage to the optic nerve. Current therapies cannot prevent glaucoma-related optic nerve disease and very little is known about the underlying responsible molecular events. Glaucoma patients affected by the “normal-pressure” subtype of glaucoma (NPG) have increased susceptibility to optic nerve degeneration. Although NPG has a high heritability, common predisposing genetic variants have not been identified. Therefore, we performed a meta-analysis of two independent genome-wide association studies for a common form of glaucoma, primary open angle glaucoma (POAG), followed by NPG subgroup analysis. We found that SNPs in the CDKN2BAS gene region on 9p21 and a highly conserved region with a probable regulatory function on 8q22 were associated with NPG and with optic nerve disease in a second type of glaucoma, exfoliation glaucoma. Both genomic regions are predicted to influence TGF-beta activity, and using whole-genome data we showed that the TGF-beta signaling pathway overall is associated with NPG. These results reveal new insights into the molecular pathogenesis of optic nerve disease in glaucoma and are an important step toward the development of preventative and protective therapies.