Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

Authors

• 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. Olson, 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

Author ORCID Identifier

https://orcid.org/0000-0003-1890-3278

https://orcid.org/0000-0002-3787-2510

https://orcid.org/0000-0003-2667-5420

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https://orcid.org/0000-0003-1414-1253

https://orcid.org/0000-0003-1315-380X

https://orcid.org/0000-0003-4435-2713

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https://orcid.org/0000-0002-8965-4267

https://orcid.org/0000-0002-2383-7263

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https://orcid.org/0000-0002-2055-5797

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https://orcid.org/0000-0003-4023-9342

https://orcid.org/0000-0003-2572-4040

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https://orcid.org/0000-0001-8394-4813

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https://orcid.org/0000-0003-2937-6987

https://orcid.org/0000-0001-6410-9388

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https://orcid.org/0000-0003-0298-6371

https://orcid.org/0000-0001-7036-2726

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Document Type

Article

Publication Date

2012

College/Unit

School of Medicine

Department/Program/Center

Ophthalmology

Abstract

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.

Digital Commons Citation

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; Stein, Joshua D.; Trager, Edward H.; VanVeldhuisen, Paul; Vollrath, Douglas; Wollstein, Gadi; Yoneyama, Sachiko; Zhang, Kang; Pasquale, Louis R.; Haines, Jonathan L.; Moroi, Sayoko E.; Musch, David C.; Realini, Anthony; Rozsa, Frank W.; Schuman, Joel S.; Scott, Kathleen; Singh, Kuldev; Weinreb, Robert N.; Ernst, Jason; Kellis, Manolis; Masuda, Tomohiro; Zack, Don; Richards, Julia E.; and Pericak-Vance, Margret, "Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma" (2012). Faculty & Staff Scholarship. 2729.
https://researchrepository.wvu.edu/faculty_publications/2729

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. https://doi.org/10.1371/journal.pgen.1002654

Comments

© 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.