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

Publication Type
Journal Article
Year of Publication
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; Moroi, Sayoko E; Musch, David C; Realini, Anthony; Rozsa, Frank W; Schuman, Joel S; Scott, Kathleen; Singh, Kuldev; Stein, Joshua D; Trager, Edward H; VanVeldhuisen, Paul; Vollrath, Douglas; Wollstein, Gadi; Yoneyama, Sachiko; Zhang, Kang; Weinreb, Robert N; Ernst, Jason; Kellis, Manolis; Masuda, Tomohiro; Zack, Don; Richards, Julia E; Pericak-Vance, Margaret; Pasquale, Louis R; Haines, Jonathan L
PLoS Genet
Date Published
Alleles; Chromosomes, Human, Pair 8; Chromosomes, Human, Pair 9; Exfoliation Syndrome; Genome-Wide Association Study; Glaucoma, Open-Angle; Homeodomain Proteins; Humans; Nerve Degeneration; Optic Nerve; Polymorphism, Single Nucleotide; RNA, Long Noncoding; RNA, Untranslated; Transforming Growth Factor beta

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.