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

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Author
Yaspan, Brian L.
Hauser, Michael A.
Allingham, R. Rand
Olson, Lana M.
Abdrabou, Wael
Brodeur, Wendy
Budenz, Donald L.
Caprioli, Joseph
Crenshaw, Andrew
Crooks, Kristy
DelBono, Elizabeth
Doheny, Kimberly F.
Gaasterland, Douglas
Gaasterland, Terry
Laurie, Cathy
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
Trager, Edward H.
VanVeldhuisen, Paul
Vollrath, Douglas
Wollstein, Gadi
Yoneyama, Sachiko
Zhang, Kang
Weinreb, Robert N.
Ernst, Jason
Masuda, Tomohiro
Zack, Don
Richards, Julia E.
Pericak-Vance, Margaret
Haines, Jonathan L.
Friedman, David S.
Lee, Richard K.
Stein, Joshua D.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1371/journal.pgen.1002654Metadata
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Wiggs, Janey L., Brian L. Yaspan, Michael A. Hauser, Jae H. Kang, R. Rand Allingham, Lana M. Olson, Wael Abdrabou, et al. 2012. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genetics 8(4): e1002654.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343074/pdf/Terms of Use
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