title: Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.
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.
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America. janey_wiggs@meei.harvard.edu
authors.forename: Janey L
authors.initials: JL
authors.lastname: Wiggs
authors.forename: Brian L
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authors.forename: Yutao
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authors.forename: Felipe A
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authors.forename: Cathy
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authors.lastname: McCarty
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authors.forename: Sayoko E
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authors.forename: Frank W
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authors.lastname: Rozsa
authors.forename: Joel S
authors.initials: JS
authors.lastname: Schuman
authors.forename: Kathleen
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authors.lastname: Scott
authors.forename: Kuldev
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authors.lastname: Singh
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Stein
authors.forename: Edward H
authors.initials: EH
authors.lastname: Trager
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authors.lastname: Vanveldhuisen
authors.forename: Douglas
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authors.lastname: Vollrath
authors.forename: Gadi
authors.initials: G
authors.lastname: Wollstein
authors.forename: Sachiko
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authors.lastname: Yoneyama
authors.forename: Kang
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authors.lastname: Zhang
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
authors.forename: Jason
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authors.lastname: Ernst
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Masuda
authors.forename: Don
authors.initials: D
authors.lastname: Zack
authors.forename: Julia E
authors.initials: JE
authors.lastname: Richards
authors.forename: Margaret
authors.initials: M
authors.lastname: Pericak-Vance
authors.forename: Louis R
authors.initials: LR
authors.lastname: Pasquale
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
mesh_terms: D000483:Alleles; D002898:Chromosomes, Human, Pair 8; D002899:Chromosomes, Human, Pair 9; D017889:Exfoliation Syndrome / Q000235:genetics*; D055106:Genome-Wide Association Study; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C561518:CDKN2B antisense RNA, human; D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C099236:SIX1 protein, human; D016212:Transforming Growth Factor beta