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Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

Nature Genetics volume 52, pages 160–166 (2020)Cite this article

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Abstract

Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10−6). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

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Fig. 1: Manhattan plot displaying glaucoma-specific P values from the MTAG analysis.
Fig. 2: Comparison of the effect sizes (log ORs) for 114 genome-wide significant independent SNPs identified from the glaucoma multiple trait analysis of GWAS in the UKB versus those in independent glaucoma cohorts (meta-analysis of ANZRAG and NEIGHBORHOOD).
Fig. 3: Multitrait analysis of GWAS PRS prediction.
Fig. 4: Clinical implications of the glaucoma PRS.

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Data availability

The UKB data are available through the UK Biobank Access Management System https://www.ukbiobank.ac.uk/. The GWAS summary statistics from the glaucoma MTAG analysis is available for research use at https://xikunhan.github.io/site/publication/. We will return the derived data fields following UKB policy; in due course, they will be available through the UK Biobank Access Management System.

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Acknowledgements

This work was conducted using the UK Biobank Resource (application no. 25331) and publicly available data from the IGGC. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and Northwest Regional Development Agency. It also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The eye and vision dataset has been developed with additional funding from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology, Fight for Sight charity, Moorfields Eye Charity, Macular Society, International Glaucoma Association and Alcon Research Institute. This work was also supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (nos. 1107098, 1116360, 1116495, 1023911, 1150144, 1147571), the Ophthalmic Research Institute of Australia, the BrightFocus Foundation, the UK and Eire Glaucoma Society and charitable funds from the Royal Liverpool University Hospital. S.M., J.E.C., K.P.B., D.A.M. and A.W.H. are supported by NHMRC Fellowships (APP1154543, APP1154824, APP1059954, APP1154513, APP1103329). S.M. was supported by an Australian Research Council Future Fellowship (FT130101902). L.R.P. is supported by National Institutes of Health grant no. R01 EY015473. X.H. is supported by the University of Queensland Research Training Scholarship and Queensland Institute of Medical Research Berghofer PhD Top Up Scholarship. We thank D. Whiteman, R. Neale and C. Olson for providing access to the QSkin samples for use as controls as part of NHMRC grant no. 1063061. We thank S. Wood, J. Pearson and S. Gordon from the Queensland Institute of Medical Research Berghofer Research Institute for their support. The NEIGHBORHOOD consortium is supported by National Institutes of Health grant nos. P30 EY014104, R01 EY015473 and R01 EY022305.

Author information

Author notes

  1. These authors contributed equally: Xikun Han, Jamie E. Craig, Ayub Qassim, Alex W. Hewitt, Stuart MacGregor.

  2. A list of members and affiliations appears in the Supplementary Note.

Authors and Affiliations

  1. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia

    Jamie E. Craig, Ayub Qassim, Mark Hassall, Henry Marshall, Tiger Zhou, Owen Siggs, Emmanuelle Souzeau, Bronwyn Ridge, Richard A. Mills, John Landers & Nicholas H. Andrew

  2. Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Xikun Han, Jiyuan An, Puya Gharahkhani, Jue-Sheng Ong, Matthew H. Law, Graham Radford-Smith, Nicholas G. Martin & Stuart MacGregor

  3. School of Medicine, University of Queensland, Brisbane, Queensland, Australia

    Xikun Han

  4. Department of Population and Quantitative Health Sciences, Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH, USA

    Jessica N. Cooke Bailey, Tyler G. Kinzy, Robert P. Igo Jr. & Jonathan L. Haines

  5. National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK

    Anthony P. Khawaja, Ananth C. Viswanathan, Paul J. Foster & Peng Tee Khaw

  6. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia

    Stuart L. Graham

  7. Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia

    Paul R. Healey & Andrew J. R. White

  8. Clinical Ophthalmology & Eye Health, Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia

    Paul R. Healey & Andrew J. R. White

  9. Department of Ophthalmology, King’s College London, St. Thomas’ Hospital, London, UK

    Pirro G. Hysi & Christopher J. Hammond

  10. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia

    Kathryn P. Burdon, David A. Mackey & Alex W. Hewitt

  11. Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia

    Jonathan B. Ruddle

  12. Department of Ophthalmology, Prince of Wales Hospital Randwick, Sydney, New South Wales, Australia

    Ashish Agar

  13. South Australian Institute of Ophthalmology, Royal Adelaide Hospital, Adelaide, South Australia, Australia

    Anna Galanopoulos

  14. Biomedical Sciences Research Institute, Ulster University, Coleraine, UK

    Colin E. Willoughby

  15. Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK

    Colin E. Willoughby

  16. Eye Department, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand

    Stephen Best

  17. Department of Ophthalmology, University of Auckland, Auckland, New Zealand

    Andrea L. Vincent

  18. Discipline of Ophthalmology, Faculty of Medicine and Health, University of Sydney, Sydney Eye Hospital, Sydney, New South Wales, Australia

    Ivan Goldberg

  19. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    Grant W. Montgomery

  20. Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    Veronique Vitart

  21. Department of Ophthalmology, University Hospital Bern, Inselspital, University of Bern, Bern, Switzerland

    Rene Hoehn

  22. Department of Ophthalmology, University Medical Center Mainz, Mainz, Germany

    Rene Hoehn

  23. Department of Epidemiology and Medicine, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Robert Wojciechowski

  24. Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Robert Wojciechowski

  25. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht-Karls-University of Heidelberg, Mannheim, Germany

    Jost B. Jonas

  26. Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore

    Tin Aung

  27. Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Louis R. Pasquale

  28. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    Angela Jane Cree & Andrew J. Lotery

  29. National Institute for Health Research Moorfields Biomedical Research Centre, London, UK

    Sobha Sivaprasad

  30. Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK

    Neeru A. Vallabh

  31. St Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, UK

    Neeru A. Vallabh

  32. Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Francesca Pasutto

  33. Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands

    Caroline C. W. Klaver

  34. Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands

    Cornelia M. van Duijn

  35. South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, South Australia, Australia

    Robert J. Casson

  36. Lions Eye Institute, Centre for Ophthalmology and Vision Sciences, University of Western Australia, Perth, Western Australia, Australia

    David A. Mackey

  37. Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia

    Paul Mitchell

  38. Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, USA

    Janey L. Wiggs

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  1. Jamie E. Craig
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  2. Xikun Han
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  3. Ayub Qassim
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  8. Jiyuan An
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  36. Veronique Vitart
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  37. Rene Hoehn
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  40. Tin Aung
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  41. Louis R. Pasquale
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  42. Angela Jane Cree
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  43. Sobha Sivaprasad
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  44. Neeru A. Vallabh
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  45. Ananth C. Viswanathan
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  52. Peng Tee Khaw
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  53. Christopher J. Hammond
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  54. David A. Mackey
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  59. Stuart MacGregor
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Consortia

NEIGHBORHOOD consortium

UK Biobank Eye and Vision Consortium

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S.M., J.E.C., A.W.H., X.H., P.G., J.L.W. and D.A.M. designed the study and obtained the funding. X.H., A.Q., M.H., J.N.C.B., T.G.K., A.P.K., P.G.H., J.A., H.M., P.G., R.P.I., J.-S.O., T.Z., O.S., M.H.L. and S.M. analyzed the data. J.E.C., X.H., A.Q., M.H., A.P.K., H.M., R.P.I., S.L.G., P.R.H., O.S., E.S., B.S., P.G.H., K.P.B., R.A.M., J.L., J.B.R., A.A., A.G., A.J.R.W., C.E.W., N.A., S.B., A.L.V., I.G., G.R.-S., N.G.M., G.W.M., V.V., R.H., R.W., J.B.J., T.A., L.R.P., A.J.C., S.S., N.A.V., A.C.V., F.P., J.L.H., C.C.W.K., C.M.v.D., R.J.C., P.J.F., P.T.K., C.J.H., D.A.M., P.M., A.J.L., J.L.W., A.W.H. and S.M. contributed to data collection and contributed to genotyping. X.H., J.E.C., A.Q., A.W.H. and S.M. wrote the first draft of the paper. All authors contributed to the final version of the paper.

Corresponding author

Correspondence to Xikun Han.

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Competing interests

D.A.M. is consultant/advisor to Allergan, Inc. J.E.C., A.W.H. and S.M. are listed as coinventors on a patent application for the use of genetic risk scores to determine risk and guide treatment.

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Extended data

Extended Data Fig. 1 Study design.

We applied the multi-trait analysis of GWAS (MTAG) algorithm to datasets of European descent (unless otherwise specified). a, We applied MTAG to four datasets (glaucoma case-control GWAS from the UKBB; GWAS meta-analysis of intraocular pressure (IOP) from the International Glaucoma Genetics Consortium (IGGC) and the UKBB; Vertical cup-disc ratio (VCDR) GWAS data that was either adjusted for vertical disc diameter (VDD) in the UKBB dataset; or not adjusted for VDD in the IGGC). Novel variants identified through this analysis were then confirmed in two independent data sets: an Australasian cohort of advanced glaucoma (ANZRAG) and a consortium of cohorts from the United States (NEIGHBORHOOD). The clinical significance of the PRS derived from the MTAG analysis was validated in independent samples: first, in advanced glaucoma cases (ANZRAG and samples from Southampton/Liverpool in the UK), and second, in a prospectively monitored clinical cohort with early manifest glaucoma (PROGRESSA). b, Prediction in BMES, where we removed the IGGC VCDR and IGGC IOP GWAS from the training datasets, given that they contain BMES data. c, Prediction in the UKBB glaucoma and ICD-10 POAG cases. Here we removed all glaucoma cases and 3,000 controls with IOP/VCDR measurements as well as their relatives from UKBB VCDR/IOP GWAS. We also evaluated the performance of PRS in non-European ancestry (192 cases and 6,841 controls of South Asian ancestry in UKBB). d, Cumulative risk of glaucoma in UKBB. For the analysis of MYOC p.Gln368Ter carriers (n = 965; cases = 72; controls = 893), participants were stratified into tertiles of PRS. We also examined cumulative risk of glaucoma in the general population (that is in MYOC p.Gln368Ter non-carriers, n = 381,196; cases = 7,381; controls = 373,815) stratifying by deciles of the PRS. The discovery and testing datasets were designed to derive the PRS with no sample overlap (Supplementary Note).

Supplementary information

Supplementary Information

Supplementary Note, Figs. 1–13 and Tables 1–13

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Craig, J.E., Han, X., Qassim, A. et al. Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression. Nat Genet 52, 160–166 (2020). https://doi.org/10.1038/s41588-019-0556-y

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