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Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma

Wiggs, JL and Yaspan, BL and Hauser, MA and Kang, JH and Allingham, RR and Olson, LM and Abdrabou, W and Fan, BJ and Wang, DY and Brodeur, W and Budenz, DL and Caprioli, J and Crenshaw, A and Crooks, K and DelBono, E and Doheny, KF and Friedman, DS and Gaasterland, D and Gaasterland, T and Laurie, C and Lee, RK and Lichter, PR and Loomis, S and Liu, Y and Medeiros, FA and McCarty, C and Mirel, D and Moroi, SE and Musch, DC and Realini, A and Rozsa, FW and Schuman, JS and Scott, K and Singh, K and Stein, JD and Trager, EH and VanVeldhuisen, P and Vollrath, D and Wollstein, G and Yoneyama, S and Zhang, K and Weinreb, RN and Ernst, J and Kellis, M and Masuda, T and Zack, D and Richards, JE and Pericak-Vance, M and Pasquale, LR and Haines, JL (2012) Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genetics, 8 (4). ISSN 1553-7390

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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. © 2012 Wiggs et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Wiggs, JL
Yaspan, BL
Hauser, MA
Kang, JH
Allingham, RR
Olson, LM
Abdrabou, W
Fan, BJ
Wang, DY
Brodeur, W
Budenz, DL
Caprioli, J
Crenshaw, A
Crooks, K
DelBono, E
Doheny, KF
Friedman, DS
Gaasterland, D
Gaasterland, T
Laurie, C
Lee, RK
Lichter, PR
Loomis, S
Liu, Y
Medeiros, FA
McCarty, C
Mirel, D
Moroi, SE
Musch, DC
Realini, A
Rozsa, FW
Schuman, JSjss28@pitt.eduJSS280000-0002-8885-3766
Scott, K
Singh, K
Stein, JD
Trager, EH
VanVeldhuisen, P
Vollrath, D
Wollstein, Gchw28@pitt.eduCHW28
Yoneyama, S
Zhang, K
Weinreb, RN
Ernst, J
Kellis, M
Masuda, T
Zack, D
Richards, JE
Pericak-Vance, M
Pasquale, LR
Haines, JL
ContributionContributors NameEmailPitt UsernameORCID
Date: 1 April 2012
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 8
Number: 4
DOI or Unique Handle: 10.1371/journal.pgen.1002654
Schools and Programs: School of Medicine > Ophthalmology
Refereed: Yes
ISSN: 1553-7390
Other ID: NLM PMC3343074
PubMed Central ID: PMC3343074
PubMed ID: 22570617
Date Deposited: 24 Sep 2012 20:25
Last Modified: 22 Jun 2021 13:55


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