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PMID: 22570617 Published · ppublish English Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

PLoS genetics ·Vol. 8 ·No. 4 ·2012-00-00 ·Pages e1002654

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 JS, Scott K, Singh K, Stein JD, Trager EH, Vanveldhuisen P, Vollrath D, Wollstein G, Yoneyama S, Zhang K, Weinreb RN, Ernst J, Kellis M, Masuda T, Zack D, Richards JE, Pericak-Vance M, Pasquale LR, Haines JL

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.

MeSH Terms
Alleles Chromosomes, Human, Pair 8 Chromosomes, Human, Pair 9 Exfoliation Syndrome/genetics Genome-Wide Association Study Glaucoma, Open-Angle/genetics Homeodomain Proteins/genetics Humans Nerve Degeneration/genetics,pathology Optic Nerve/pathology Polymorphism, Single Nucleotide RNA, Long Noncoding RNA, Untranslated/genetics Transforming Growth Factor beta/genetics,metabolism
Chemicals
CDKN2B antisense RNA, human Homeodomain Proteins RNA, Long Noncoding RNA, Untranslated SIX1 protein, human Transforming Growth Factor beta
Authors & Affiliations
50 authors, click to expand affiliations / ORCID
Wiggs Janey L
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America. [email protected]
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
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002654
Email
[email protected]
Published
2012-00-00
Epub
2012-00-26
Pages
e1002654
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3343074
Subset
IM
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External Links
PubMed source DOI: 10.1371/journal.pgen.1002654 PMC Full Text View journal details
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