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; Olsen, 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.