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

Abstract

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.

Primary cilia signaling mediates intraocular pressure sensation

“…TNF-α and TGF-β are both highly abundant in the aqueous humor of patients with both acute and chronic forms of glaucoma (33)(34)(35). To determine whether the expression of TNF-α was up-regulated in response to pressure, its transcript levels were measured by quantitative RT-PCR (qRT-PCR) under different pressures.…”

Expansive marker analysis replicating the association of glaucoma susceptibility with human chromosome loci 1q43 and 10p12.31

“…Recently, several POAG susceptibility loci were identified by genome-wide association (GWA) studies [16][17][18][19][20] and were replicated in multiple ethnicities: 7q31.2 between CAV1 and CAV2, 16,21 9p21.3 with CDKN2B-AS1, 19,20,[22][23][24][25][26] 10q21.3 with ATOH7, 17,18,22,27 and 14q23.1 between SIX1 and SIX6. 17,20,22,28 One of the GWA studies demonstrated the association of POAG with six SNPs that flanked the ZP4, PLXDC2, and TMTC2 genes located at chromosome loci 1q43, 10p12.31, and 12q21.31, respectively, in a Japanese population; 29 however, these associations were not replicated in a South Indian, 30 Afro-Caribbean, 24 or Chinese 31 population.…”

Pathway analysis by randomization incorporating structure—PARIS: an update

“…We executed PARIS on GWAS results from 480 k SNPs evaluated by the NEIGHBOR consortium (Bailey et al, 2014;Wiggs et al, 2012). Comparing results from a prior version of PARIS (1.1.3) to this new version (2.4), results are highly correlated (Fig.…”