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Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma


We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10−10). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.

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Figure 1: The 7q31 locus.


  1. Resnikoff, S. et al. Global data on visual impairment in the year 2002. Bull. World Health Organ. 82, 844–851 (2004).

    PubMed  PubMed Central  Google Scholar 

  2. Allingham, R.R., Liu, Y. & Rhee, D.J. The genetics of primary open-angle glaucoma: a review. Exp. Eye Res. 88, 837–844 (2009).

    CAS  Article  Google Scholar 

  3. Fan, B.J., Wang, D.Y., Lam, D.S. & Pang, C.P. Gene mapping for primary open angle glaucoma. Clin. Biochem. 39, 249–258 (2006).

    CAS  Article  Google Scholar 

  4. Stone, E.M. et al. Identification of a gene that causes primary open angle glaucoma. Science 275, 668–670 (1997).

    CAS  Article  Google Scholar 

  5. Rezaie, T. et al. Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295, 1077–1079 (2002).

    CAS  Article  Google Scholar 

  6. Monemi, S. et al. Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1. Hum. Mol. Genet. 14, 725–733 (2005).

    CAS  Article  Google Scholar 

  7. Pasutto, F. et al. Heterozygous NTF4 mutations impairing neurotrophin-4 signaling in patients with primary open-angle glaucoma. Am. J. Hum. Genet. 85, 447–456 (2009).

    CAS  Article  Google Scholar 

  8. Thorleifsson, G. et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 317, 1397–1400 (2007).

    CAS  Article  Google Scholar 

  9. Liu, Y. et al. Lack of association between LOXL1 variants and primary open-angle glaucoma in three different populations. Invest. Ophthalmol. Vis. Sci. 49, 3465–3468 (2008).

    Article  Google Scholar 

  10. Nakano, M. et al. Three susceptible loci associated with primary open-angle glaucoma identified by genome-wide association study in a Japanese population. Proc. Natl. Acad. Sci. USA 106, 12838–12842 (2009).

    CAS  Article  Google Scholar 

  11. Rao, K.N., Kaur, I. & Chakrabarti, S. Lack of association of three primary open-angle glaucoma-susceptible loci with primary glaucomas in an Indian population. Proc. Natl. Acad. Sci. USA 106, E125–126 (2009). author reply 106, E127 (2009).

    CAS  Article  Google Scholar 

  12. Jonasson, F. et al. Prevalence of open-angle glaucoma in Iceland: Reykjavik Eye Study. Eye (Lond) 17, 747–753 (2003).

    CAS  Article  Google Scholar 

  13. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

    CAS  Article  Google Scholar 

  14. Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).

    CAS  Article  Google Scholar 

  15. Mackey, D.A. et al. Twins eye study in tasmania (TEST): rationale and methodology to recruit and examine twins. Twin Res. Hum. Genet. 12, 441–454 (2009).

    Article  Google Scholar 

  16. Tamm, E.R. The trabecular meshwork outflow pathways: structural and functional aspects. Exp. Eye Res. 88, 648–655 (2009).

    CAS  Article  Google Scholar 

  17. Gonzalez, P., Epstein, D.L. & Borras, T. Characterization of gene expression in human trabecular meshwork using single-pass sequencing of 1,060 clones. Invest. Ophthalmol. Vis. Sci. 41, 3678–3693 (2000).

    CAS  PubMed  Google Scholar 

  18. Berta, A.I. et al. Different caveolin isoforms in the retina of melanoma malignum affected human eye. Mol. Vis. 13, 881–886 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Borrás, T. Gene expression in the trabecular meshwork and the influence of intraocular pressure. Prog. Retin. Eye Res. 22, 435–463 (2003).

    Article  Google Scholar 

  20. Couet, J., Belanger, M.M., Roussel, E. & Drolet, M.C. Cell biology of caveolae and caveolin. Adv. Drug Deliv. Rev. 49, 223–235 (2001).

    CAS  Article  Google Scholar 

  21. Hnasko, R. & Lisanti, M.P. The biology of caveolae: lessons from caveolin knockout mice and implications for human disease. Mol. Interv. 3, 445–464 (2003).

    CAS  Article  Google Scholar 

  22. Patel, H.H., Murray, F. & Insel, P.A. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu. Rev. Pharmacol. Toxicol. 48, 359–391 (2008).

    CAS  Article  Google Scholar 

  23. Parat, M.O. The biology of caveolae: achievements and perspectives. Int. Rev. Cell. Mol. Biol. 273, 117–162 (2009).

    CAS  Article  Google Scholar 

  24. Jasmin, J.F., Yang, M., Iacovitti, L. & Lisanti, M.P. Genetic ablation of caveolin-1 increases neural stem cell proliferation in the subventricular zone (SVZ) of the adult mouse brain. Cell Cycle 8, 3978–3983 (2009).

    CAS  Article  Google Scholar 

  25. Ju, H., Zou, R., Venema, V.J. & Venema, R.C. Direct interaction of endothelial nitric-oxide synthase and caveolin-1 inhibits synthase activity. J. Biol. Chem. 272, 18522–18525 (1997).

    CAS  Article  Google Scholar 

  26. García-Cardeña, G. et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J. Biol. Chem. 272, 25437–25440 (1997).

    Article  Google Scholar 

  27. Fuchshofer, R. & Tamm, E.R. Modulation of extracellular matrix turnover in the trabecular meshwork. Exp. Eye Res. 88, 683–688 (2009).

    CAS  Article  Google Scholar 

  28. Toda, N. & Nakanishi-Toda, M. Nitric oxide: ocular blood flow, glaucoma, and diabetic retinopathy. Prog. Retin. Eye Res. 26, 205–238 (2007).

    CAS  Article  Google Scholar 

  29. Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    CAS  Article  Google Scholar 

  30. Holm, H. et al. Several common variants modulate heart rate, PR interval and QRS duration. Nat. Genet. 42, 117–122 (2010).

    CAS  Article  Google Scholar 

  31. Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    CAS  Article  Google Scholar 

  32. Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

    CAS  Article  Google Scholar 

  33. Rice, J.A. Mathematical Statistics and Data Analysis (Wadsworth Inc., Belmond, California, USA, 1995).

  34. Mantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).

    CAS  PubMed  Google Scholar 

  35. Stefansson, H. et al. A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 (2005).

    CAS  Article  Google Scholar 

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We thank all the participants whose contribution made this study possible, as well as their ophthalmologists. We also thank the personnel at deCODE recruitment center and core facilities for their hard work and enthusiasm. We would also like to acknowledge A. Hill (University Hospitals of Leicester National Health Service (NHS) Trust) for invaluable help with sample collection and the Wellcome Trust for funding (programme grant 062346/Z/00/Z and project grant 078751/Z/05/Z). The authors acknowledge financial support from the UK Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. We also thank the following organizations for their financial support: Clifford Craig Medical Research Trust; Ophthalmic Research Institute of Australia; Pfizer Australia; Glaucoma Australia; American Health Assistance Foundation; the glaucoma research foundation and the Australian National Health and Medical Research Council (NHMRC); the International Glaucoma Association, UK and the Eire Glaucoma Society and Optegra UK Ltd. J.E.C. is supported in part by an NHMRC Practitioner Fellowship, and D.A.M. is a Pfizer Australia Research Fellow. We would also like to thank O. Wallerman, M. Jansson, L.-I. Larsson and L. Tomic for their assistance and the Swedish Research Council for financial support. The authors acknowledge the funding and support of the following organizations: the US National Institutes of Health (NIH)/National Eye Institute grant 1RO1EY018246 and the NIH Center for Inherited Diseases Research (CIDR) (PI: T. Young); the Verto Institute, the American Health Assistance Foundation (AHAF) National Glaucoma Research and the Ellison Foundation for Aging Research; and the Southampton Wellcome Trust Clinical Research Facility. We thank D.R. Nyholt, G. Montgomery, S. Medland, S. Gordon, A. Henders, B. McEvoy, M.J. Wright, M.J. Campbell and A. Caracella for obtaining funding for and processing the Australian genotype data. S.M. is supported by an Australian NHMRC Career Development Award.

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Authors and Affiliations



The study was designed, the results interpreted and the first draft written by G.T., U.T., F.J. and K.S. The statistical analysis was performed by G.T., A.W.H. and A.K. A. Jonasdottir, A.S. and S.A.G. did the bioinformatic analysis of the 7q31 region, A.H. did the phylogenetic analysis and G.M. did the imputation. Genotyping at deCODE genetics was supervised by G.B.W. and U.T. Those responsible for case and control ascertainment, recruitment and phenotype information were F.J., G.J.G., H.S., K.P.M., M.S.G. and O.S. (Icelandic POAG cases and controls); K.P.M. and K.T. (Icelandic myopia cases); L.S., M.A.A., R.C.T. and W.S.S.K. (Leicester POAG cases); D.A.C. and D.St.C. (controls used for Leicester cases); A. Jacob, A.J.C., A.J.L., A.M. J.G. and S.E. (Southampton POAG cases and controls); C.W. (Swedish POAG cases and controls); P.M., C.J.H., N.G.M., S.M., T.L.Y., A.W.H., J.E.C., K.P.B. and D.A.M. (Australian POAG cases and controls and collection, genotyping and analysis of the Australian Twin study); C.P.P., D.S.C.L., P.O.S.T., A.D.W., J.H. and M.Z. (collection and genotyping of Hong Kong and Shantou POAG cases and unaffected controls); and J.C.N.C. and N.T. (population controls from Hong Kong). All authors contributed to the final version of the paper.

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Correspondence to Gudmar Thorleifsson or Kari Stefansson.

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Competing interests

Authors whose affiliations are listed as deCODE Genetics are employees of deCODE Genetics, a biotechnology company. deCODE Genetics intends to incorporate the variants described in this paper into its genetic testing services.

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Supplementary Note, Supplementary Figures 1 and 2 and Supplmentary Tables 1–6. (PDF 407 kb)

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Thorleifsson, G., Walters, G., Hewitt, A. et al. Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 42, 906–909 (2010).

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