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

Jamie E. Craig, Xikun Han, Ayub Qassim, Mark Hassall, Jessica N. Cooke Bailey, Tyler G. Kinzy, Anthony P. Khawaja, Jiyuan An, Henry Marshall, Puya Gharahkhani, Robert P. Igo, Stuart L. Graham, Paul R. Healey, Jue-sheng Ong, Tiger Zhou, Owen Siggs, Matthew H. Law, Emmanuelle Souzeau, Bronwyn Ridge, Pirro G. HysiKathryn P. Burdon, Richard A. Mills, John Landers, Jonathan B. Ruddle, Ashish Agar, Anna Galanopoulos, Andrew J. R. White, Colin E. Willoughby, Nicholas H. Andrew, Stephen Best, Andrea L. Vincent, Ivan Goldberg, Graham Radford-smith, Nicholas G. Martin, Grant W. Montgomery, Veronique Vitart, Rene Hoehn, Robert Wojciechowski, Jost B. Jonas, Tin Aung, Louis R. Pasquale, Angela Jane Cree, Sobha Sivaprasad, Neeru A. Vallabh, Ananth C. Viswanathan, Francesca Pasutto, Jonathan L. Haines, Caroline C. W. Klaver, Cornelia M. Van Duijn, Robert J. Casson, Paul J. Foster, Peng Tee Khaw, Christopher J. Hammond, David A. Mackey, Paul Mitchell, Andrew J. Lotery, Janey L. Wiggs, Alex W. Hewitt, Stuart Macgregor

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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.
Original languageEnglish
Pages (from-to)160-166
Number of pages7
JournalNature Genetics
Issue number2
Early online date20 Jan 2020
Publication statusPublished (in print/issue) - 29 Feb 2020

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.


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