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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • 2012

Published In

Volume / Issue

  • 8 / 4

Start / End Page

  • e1002654 -

PubMed ID

  • 22570617

Pubmed Central ID

  • PMC3343074

Electronic International Standard Serial Number (EISSN)

  • 1553-7404

Digital Object Identifier (DOI)

  • 10.1371/journal.pgen.1002654


  • eng

Conference Location

  • United States