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

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

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.

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