Janey L. Wiggs, Harvard University
Brian L. Yaspan, Vanderbilt University
Michael A. Hauser, Duke University
Jae H. Kang, Brigham and Women's Hospital
R Rand Allingham, Duke University
Lana M. Olsen, Vanderbilt University
Wael Abdrabou, Harvard University
Bao J. Fan, Harvard University
Dan Y. Wang, Harvard University
Wendy Brodeur, Broad Institute of Harvard and Massachusetts Institute of Technology
Donald L. Budenz, University of North Carolina
Joseph Caprioli, University of California Los Angeles
Andrew Crenshaw, Broad Institute of Harvard and Massachusetts Institute of Technology,
Kristy Crooks, Duke University
Elizabeth DelBono, Harvard University
Kimberly F. Doheny, The Johns Hopkins University
David S. Friedman, Johns Hopkins University
Douglas Gaasterland, Eye Doctors of Washington D.C
Terry Gaasterland, University of California - San Diego
Cathy Laurie, University of Washington
Richard K. Lee, University of Miami
Paul R. Lichter, The University Of Michigan
Stephanie Loomis, Harvard University
Yutao Liu, Duke University
Felipe A. Medeiros, University of California - San Diego
Cathy McCarty, Essentia Institute of Rural Health
Daniel Mirel, Broad Institute of Harvard and Massachusetts Institute of Technology,
Joshua D. Stein, University of Michigan-Ann Arbor
Edward H. Trager, The University Of Michigan
Paul VanVeldhuisen, The EMMES Corporation
Douglas Vollrath, Stanford University
Gadi Wollstein, University of Pittsburgh
Sachiko Yoneyama, The University Of Michigan
Kang Zhang, University of California San Diego
Louis R. Pasquale, Harvard University
Jonathan L. Haines, Vanderbilt University
Sayoko E. Moroi, The University Of Michigan
David C. Musch, The University Of Michigan
Anthony Realini, West Virginia University
Frank W. Rozsa, The University Of Michigan
Joel S. Schuman, University of Pittsburgh
Kathleen Scott, The University Of Michigan
Kuldev Singh, Stanford University
Robert N. Weinreb, University of California San Diego
Jason Ernst, Broad Institute of Harvard and Massachusetts Institute of Technology
Manolis Kellis, Broad Institute of Harvard and Massachusetts Institute of Technology
Tomohiro Masuda, Johns Hopkins University
Don Zack, Johns Hopkins University
Julia E. Richards, The University Of Michigan
Margret Pericak-Vance, University of Miami

Document Type


Publication Date



School of Medicine




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.

Source Citation

Wiggs JL, Yaspan BL, Hauser MA, Kang JH, Allingham RR, Olson LM, et al. (2012) Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma. PLoS Genet 8(4): e1002654.


© 2012 Wiggs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



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