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.
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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.
Supplementary Figures 1 and 2, Supplementary Tables 1–5 and Supplementary Note.