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 LaurieRichard 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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbere1002654
JournalPLoS genetics
Issue number4
StatePublished - Apr 2012

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research


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