PLoS Genetics (Jan 2012)

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

  • Janey L Wiggs,
  • Brian L Yaspan,
  • Michael A Hauser,
  • Jae H Kang,
  • R Rand Allingham,
  • Lana M Olson,
  • Wael Abdrabou,
  • Bao J Fan,
  • Dan Y Wang,
  • Wendy Brodeur,
  • Donald L Budenz,
  • Joseph Caprioli,
  • Andrew Crenshaw,
  • Kristy Crooks,
  • Elizabeth Delbono,
  • Kimberly F Doheny,
  • David S Friedman,
  • Douglas Gaasterland,
  • Terry Gaasterland,
  • Cathy Laurie,
  • Richard K Lee,
  • Paul R Lichter,
  • Stephanie Loomis,
  • Yutao Liu,
  • Felipe A Medeiros,
  • Cathy McCarty,
  • Daniel Mirel,
  • Sayoko E Moroi,
  • David C Musch,
  • Anthony Realini,
  • Frank W Rozsa,
  • Joel S Schuman,
  • Kathleen Scott,
  • Kuldev Singh,
  • Joshua D Stein,
  • Edward H Trager,
  • Paul Vanveldhuisen,
  • Douglas Vollrath,
  • Gadi Wollstein,
  • Sachiko Yoneyama,
  • Kang Zhang,
  • Robert N Weinreb,
  • Jason Ernst,
  • Manolis Kellis,
  • Tomohiro Masuda,
  • Don Zack,
  • Julia E Richards,
  • Margaret Pericak-Vance,
  • Louis R Pasquale,
  • Jonathan L Haines

DOI
https://doi.org/10.1371/journal.pgen.1002654
Journal volume & issue
Vol. 8, no. 4
p. e1002654

Abstract

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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.