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Meta-Analysis
. 2012;8(4):e1002654.
doi: 10.1371/journal.pgen.1002654. Epub 2012 Apr 26.

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

Janey L Wiggs  1 , Brian L Yaspan, Michael A Hauser, Jae H Kang, R Rand Allingham, Lana M Olson, Wael Abdrabou, Bao J Fan, Dan Y Wang, Wendy Brodeur, Donald L Budenz, Joseph Caprioli, Andrew Crenshaw, Kristy Crooks, Elizabeth Delbono, Kimberly F Doheny, David S Friedman, Douglas Gaasterland, Terry Gaasterland, Cathy Laurie, Richard K Lee, Paul R Lichter, Stephanie Loomis, Yutao Liu, Felipe A Medeiros, Cathy McCarty, Daniel Mirel, Sayoko E Moroi, David C Musch, Anthony Realini, Frank W Rozsa, Joel S Schuman, Kathleen Scott, Kuldev Singh, Joshua D Stein, Edward H Trager, Paul Vanveldhuisen, Douglas Vollrath, Gadi Wollstein, Sachiko Yoneyama, Kang Zhang, Robert N Weinreb, Jason Ernst, Manolis Kellis, Tomohiro Masuda, Don Zack, Julia E Richards, Margaret Pericak-Vance, Louis R Pasquale, Jonathan L Haines
Affiliations
Meta-Analysis

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

Janey L Wiggs et al. PLoS Genet. 2012.

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Genome-wide association results with normal pressure glaucoma (NPG) (IOP <22 mm Hg) in the GLAUGEN-NEIGHBOR meta-analysis (720 cases and 3487 controls).
The red line identifies a p-value of 5×10−8. Covariates include: (NEIGHBOR) age, gender, study site and eigenvectors 1 and 2; (GLAUGEN) age, gender, study site, DNA extraction method, DNA specimen type and eigenvectors 1, 2 and 6.
Figure 2
Figure 2. Meta-analysis results for SNPs associated with normal pressure glaucoma (NPG) (IOP <22 mmHg) located in the CDKN2BAS region on chromosome 9p21.
The most significant SNP (rs2157719, p = 1.17×10−12) is indicated with a solid diamond.
Figure 3
Figure 3. Meta-analysis results for SNPs associated with normal pressure glaucoma (NPG) (IOP <22 mm Hg) located in the 8q22 region.
The most significant SNP (rs284489, p = 8.8×10−10) is indicated with a solid diamond.
See this image and copyright information in PMC

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