Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

Nature Genetics volume 43, pages 574–578 (2011)Cite this article

Subjects

Abstract

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10−10) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10−9). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10−14, OR = 1.51, 95% CI 1.35–1.68; rs4977756 combined P = 1.35 × 10−14, OR = 1.39, 95% CI 1.28–1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Association results for genotyped SNPs.
Figure 2: Association results for SNPs at the genome-wide significant loci corrected for λ = 1.06.
Figure 3: Ocular expression of the genes at the glaucoma-associated loci.
Figure 4: Expression of genes at the glaucoma-associated loci in a rat model of glaucoma.

Similar content being viewed by others

References

  1. Quigley, H.A. & Broman, A.T. The number of people with glaucoma worldwide in 2010 and 2020. Br. J. Ophthalmol. 90, 262–267 (2006).

    Article  CAS  Google Scholar 

  2. Heijl, A. et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch. Ophthalmol. 120, 1268–1279 (2002).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. 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).

    Article  CAS  Google Scholar 

  5. Rao, K.N. et al. Variations in NTF4, VAV2, and VAV3 genes are not involved with primary open-angle and primary angle-closure glaucomas in an indian population. Invest. Ophthalmol. Vis. Sci. 51, 4937–4941 (2010).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Green, C.M. et al. How significant is a family history of glaucoma? Experience from the Glaucoma Inheritance Study in Tasmania. Clin. Experiment. Ophthalmol. 35, 793–799 (2007).

    Article  Google Scholar 

  8. Hewitt, A.W. et al. Sensitivity of confocal laser tomography versus optical coherence tomography in detecting advanced glaucoma. Clin. Experiment. Ophthalmol. 37, 836–841, quiz 903–904 (2009).

    Article  Google Scholar 

  9. Painter, J. et al. Genome-wide association study identifies a locus at 7p15.2 associated with the development of endometriosis. Nat. Genet. 43, 51–54 (2010).

    Article  Google Scholar 

  10. Beavis, W. The power and deceit of QTL experiments: lessons from comparative QTL studies. in Proceedings of the Corn and Sorghum Industry Research Conference 250–266 (American Seed Trade Association, Washington, D.C., USA, 1994).

  11. Folkersen, L. et al. Relationship between CAD risk genotype in the chromosome 9p21 locus and gene expression. Identification of eight new ANRIL splice variants. PLoS ONE 4, e7677 (2009).

    Article  Google Scholar 

  12. Pasmant, E. et al. Characterization of a germ-line deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res. 67, 3963–3969 (2007).

    Article  CAS  Google Scholar 

  13. Ebneter, A., Casson, R.J., Wood, J.P. & Chidlow, G. Microglial activation in the visual pathway in experimental glaucoma: spatiotemporal characterization and correlation with axonal injury. Invest. Ophthalmol. Vis. Sci. 51, 6448–6460 (2010).

    Article  Google Scholar 

  14. Xin, B. et al. Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation. Proc. Natl. Acad. Sci. USA 107, 258–263 (2010).

    Article  CAS  Google Scholar 

  15. Iwamuro, S., Saeki, M. & Kato, S. Multi-ubiquitination of a nascent membrane protein produced in a rabbit reticulocyte lysate. J. Biochem. 126, 48–53 (1999).

    Article  CAS  Google Scholar 

  16. Zhang, Z. et al. Molecular cloning, expression patterns and subcellular localization of porcine TMCO1 gene. Mol. Biol. Rep. 37, 1611–1618 (2010).

    Article  CAS  Google Scholar 

  17. Helgadottir, A. et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316, 1491–1493 (2007).

    Article  CAS  Google Scholar 

  18. Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).

    Article  CAS  Google Scholar 

  19. Bilguvar, K. et al. Susceptibility loci for intracranial aneurysm in European and Japanese populations. Nat. Genet. 40, 1472–1477 (2008).

    Article  CAS  Google Scholar 

  20. Shete, S. et al. Genome-wide association study identifies five susceptibility loci for glioma. Nat. Genet. 41, 899–904 (2009).

    Article  CAS  Google Scholar 

  21. Jarinova, O. et al. Functional analysis of the chromosome 9p21.3 coronary artery disease risk locus. Arterioscler. Thromb. Vasc. Biol. 29, 1671–1677 (2009).

    Article  CAS  Google Scholar 

  22. Gonzalez, S. & Serrano, M. A new mechanism of inactivation of the INK4/ARF locus. Cell Cycle 5, 1382–1384 (2006).

    Article  CAS  Google Scholar 

  23. Williams, T.M. et al. Combined loss of INK4a and caveolin-1 synergistically enhances cell proliferation and oncogene-induced tumorigenesis: role of INK4a/CAV-1 in mammary epithelial cell hyperplasia. J. Biol. Chem. 279, 24745–24756 (2004).

    Article  CAS  Google Scholar 

  24. Ramdas, W.D. et al. A genome-wide association study of optic disc parameters. PLoS Genet. 6, e1000978 (2010).

    Article  Google Scholar 

  25. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  Google Scholar 

  26. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

  27. Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. 10, 387–406 (2009).

    Article  CAS  Google Scholar 

  28. Pruim, R. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).

    Article  CAS  Google Scholar 

  29. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  Google Scholar 

  30. R Development Core Team. R: A Language and Environment for Statistical Computing. (R Foundation for Statistical Computing, Vienna, Austria, 2008).

  31. Pfaffl, M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was funded by the National Health and Medical Research Council (NHMRC) of Australia, project grant 535074 to J.E.C., A.W.H., S.M., D.A.M. and K.P.B. We also thank the following organizations for their financial support: Royal Australian and New Zealand College of Ophthalmologists (RANZCO) Eye Foundation, Clifford Craig Medical Research Trust, Ophthalmic Research Institute of Australia (ORIA), Pfizer Australia, Glaucoma Australia, American Health Assistance Foundation (AHAF), Peggy and Leslie Cranbourne Foundation, Jack Brockhoff Foundation, and National Eye Institute (NEI) Project Grant (2007-2010). The Australian Twin Registry is supported by an NHMRC Enabling Grant (2004-2009). The Queensland Institute of Medical Research (QIMR) Study was also supported by grants from the NHMRC (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485 and 552498), the Cooperative Research Centre for Discovery of Genes for Common Human Diseases, Cerylid Biosciences (Melbourne) and donations from N. and S. Hawkins.

S.M. and K.P.B. are supported by NHMRC Career Development Awards (496674, 613705 and 595944). D.R.N. was supported by the NHMRC Fellowship (339462 and 613674) and Australian Research Council Future Fellowship (FT0991022) schemes. G.W.M., M.A.B. and J.E.C. are supported by the NHMRC Fellowships Scheme. D.A.M. is a recipient of the Pfizer Australia Senior Research Fellowship.

We thank all participants of the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG), the Glaucoma Inheritance Study in Tasmania (GIST), the Blue Mountains Eye study (BMES), the Queensland Institute of Medical Research (QIMR) study, Oxford Endometriosis Gene Study (OXEGENE), the Nurses Health Study (NHS) and the Brisbane Adolescent Twin Study (BATS) and the staff who have collated clinical data and DNA samples over many years. We thank Glaucoma Australia and Endometriosis Associations for supporting study recruitment. We thank S. Nicolaides, Queensland Medical Laboratory and SA Pathology for pro bono collection and delivery of blood samples and other pathology services for assistance with blood collection.

We thank B. Usher, S. Thorpe, A. Kuot, A. McMellon, M. Ring, T. Straga, L. Kearns, J. Barbour, S. Staffieri, J. Ruddle, P. Coleman, M.J. Wright, M.J. Campbell, A. Caracella, L. Bowdler, S. Smith, S. Gordon, K. Zondervan, S. Treloar, J. Painter, B. Haddon, D. Smyth, H. Beeby, O. Zheng and B. Chapman for their input to project management, databases, sample and data collection, sample processing and genotyping. We are grateful to the many research assistants and interviewers for assistance with the studies contributing to the collections used in this project.

We gratefully acknowledge the use of the Wellcome Trust Case Control Consortium 1958 British Birth Cohort data.

Author information

Author notes

  1. Kathryn P Burdon, Stuart Macgregor and Alex W Hewitt: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia

    Kathryn P Burdon, Alex W Hewitt, Shiwani Sharma, Richard A Mills, John Landers, Emmanuelle Souzeau, April Crawford & Jamie E Craig

  2. Genetics and Population Health, Queensland Institute of Medical Research, Brisbane, Australia

    Stuart Macgregor, Jimmy Z Liu, Anjali K Henders, Dale R Nyholt, Nicholas G Martin & Grant W Montgomery

  3. Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Australia

    Alex W Hewitt, Jie Jin Wang & David A Mackey

  4. South Australian Institute of Ophthalmology, Hanson Institute and Adelaide University, Adelaide, South Australia, Australia

    Glyn Chidlow, Robert Casson & John Wood

  5. The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia

    Patrick Danoy, Paul Leo & Matthew A Brown

  6. Moorfields Eye Hospital, London, UK

    Ananth C Viswanathan

  7. Department of Ophthalmology and Westmead Millennium Institute, Centre for Vision Research, University of Sydney, Westmead, Australia

    Jie Jin Wang, Elena Rochtchina & Paul Mitchell

  8. Lions Eye Institute, University of Western Australia, Centre for Ophthalmology and Visual Science, Perth, Australia

    David A Mackey

  9. Discipline of Medicine, University of Tasmania, Hobart, Australia

    David A Mackey

Authors
  1. Kathryn P Burdon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stuart Macgregor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alex W Hewitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shiwani Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Glyn Chidlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard A Mills
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patrick Danoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert Casson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ananth C Viswanathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jimmy Z Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. John Landers
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anjali K Henders
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. John Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Emmanuelle Souzeau
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. April Crawford
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Paul Leo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Jie Jin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Elena Rochtchina
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Dale R Nyholt
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Nicholas G Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Grant W Montgomery
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Paul Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Matthew A Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. David A Mackey
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Jamie E Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.P.B., S.M., A.W.H., D.A.M. and J.E.C. were involved in the concept and design of this study. A.W.H., R.A.M., R.C., J.L., E.S., J.J.W., N.G.M., G.W.M., P.M., D.A.M. and J.E.C. recruited participants. Genotyping was performed by K.P.B., P.D., A.C.V., A.K.H., J.J.W., D.R.N., N.G.M., G.W.M., M.A.B. and J.E.C. Statistical analysis was undertaken by K.P.B., S.M., J.Z.L., P.L., E.R., D.R.N. and M.A.B. Direct sequencing was performed by K.P.B. and A.C., S.S., G.C., R.C. and J.W. performed the immunohistochemistry and gene expression studies. K.P.B., S.M. and J.E.C. wrote the initial draft. All authors critically revised and provided final approval of this manuscript.

Corresponding author

Correspondence to Jamie E Craig.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2, Supplementary Tables 1–5 and Supplementary Note. (PDF 519 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burdon, K., Macgregor, S., Hewitt, A. et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 43, 574–578 (2011). https://doi.org/10.1038/ng.824

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.824

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing