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Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

  • Author(s): Wiggs, JL
  • Yaspan, BL
  • Hauser, MA
  • Kang, JH
  • Allingham, RR
  • Olson, LM
  • Abdrabou, W
  • Fan, BJ
  • Wang, DY
  • Brodeur, W
  • Budenz, DL
  • Caprioli, J
  • Crenshaw, A
  • Crooks, K
  • DelBono, E
  • Doheny, KF
  • Friedman, DS
  • Gaasterland, D
  • Gaasterland, T
  • Laurie, C
  • Lee, RK
  • Lichter, PR
  • Loomis, S
  • Liu, Y
  • Medeiros, FA
  • McCarty, C
  • Mirel, D
  • Moroi, SE
  • Musch, DC
  • Realini, A
  • Rozsa, FW
  • Schuman, JS
  • Scott, K
  • Singh, K
  • Stein, JD
  • Trager, EH
  • VanVeldhuisen, P
  • Vollrath, D
  • Wollstein, G
  • Yoneyama, S
  • Zhang, K
  • Weinreb, RN
  • Ernst, J
  • Kellis, M
  • Masuda, T
  • Zack, D
  • Richards, JE
  • Pericak-Vance, M
  • Pasquale, LR
  • Haines, JL
  • et al.
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. © 2012 Wiggs et al.

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