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. Hysi; Kathryn 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

doi:10.1038/s41588-019-0556-y

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

School of Biomedical Sciences

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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.

Original language	English
Pages (from-to)	160-166
Number of pages	7
Journal	Nature Genetics
Volume	52
Issue number	2
DOIs	https://doi.org/10.1038/s41588-019-0556-y
Publication status	Published - 20 Jan 2020

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Craig, J. E., Han, X., Qassim, A., Hassall, M., Cooke Bailey, J. N., Kinzy, T. G., Khawaja, A. P., An, J., Marshall, H., Gharahkhani, P., Igo, R. P., Graham, S. L., Healey, P. R., Ong, J., Zhou, T., Siggs, O., Law, M. H., Souzeau, E., Ridge, B., ... Macgregor, S. (2020). Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression. Nature Genetics, 52(2), 160-166. https://doi.org/10.1038/s41588-019-0556-y

Craig, Jamie E. ; Han, Xikun ; Qassim, Ayub ; Hassall, Mark ; Cooke Bailey, Jessica N. ; Kinzy, Tyler G. ; Khawaja, Anthony P. ; An, Jiyuan ; Marshall, Henry ; Gharahkhani, Puya ; Igo, Robert P. ; Graham, Stuart L. ; Healey, Paul R. ; Ong, Jue-sheng ; Zhou, Tiger ; Siggs, Owen ; Law, Matthew H. ; Souzeau, Emmanuelle ; Ridge, Bronwyn ; Hysi, Pirro G. ; Burdon, Kathryn P. ; Mills, Richard A. ; Landers, John ; Ruddle, Jonathan B. ; Agar, Ashish ; Galanopoulos, Anna ; White, Andrew J. R. ; Willoughby, Colin E. ; Andrew, Nicholas H. ; Best, Stephen ; Vincent, Andrea L. ; Goldberg, Ivan ; Radford-smith, Graham ; Martin, Nicholas G. ; Montgomery, Grant W. ; Vitart, Veronique ; Hoehn, Rene ; Wojciechowski, Robert ; Jonas, Jost B. ; Aung, Tin ; Pasquale, Louis R. ; Cree, Angela Jane ; Sivaprasad, Sobha ; Vallabh, Neeru A. ; Viswanathan, Ananth C. ; Pasutto, Francesca ; Haines, Jonathan L. ; Klaver, Caroline C. W. ; Van Duijn, Cornelia M. ; Casson, Robert J. ; Foster, Paul J. ; Khaw, Peng Tee ; Hammond, Christopher J. ; Mackey, David A. ; Mitchell, Paul ; Lotery, Andrew J. ; Wiggs, Janey L. ; Hewitt, Alex W. ; Macgregor, Stuart. / Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression. In: Nature Genetics. 2020 ; Vol. 52, No. 2. pp. 160-166.

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title = "Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression",

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.",

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

year = "2020",

month = jan,

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doi = "10.1038/s41588-019-0556-y",

language = "English",

volume = "52",

pages = "160--166",

journal = "Nature Genetics",

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Craig, JE, Han, X, Qassim, A, Hassall, M, Cooke Bailey, JN, Kinzy, TG, Khawaja, AP, An, J, Marshall, H, Gharahkhani, P, Igo, RP, Graham, SL, Healey, PR, Ong, J, Zhou, T, Siggs, O, Law, MH, Souzeau, E, Ridge, B, Hysi, PG, Burdon, KP, Mills, RA, Landers, J, Ruddle, JB, Agar, A, Galanopoulos, A, White, AJR, Willoughby, CE, Andrew, NH, Best, S, Vincent, AL, Goldberg, I, Radford-smith, G, Martin, NG, Montgomery, GW, Vitart, V, Hoehn, R, Wojciechowski, R, Jonas, JB, Aung, T, Pasquale, LR, Cree, AJ, Sivaprasad, S, Vallabh, NA, Viswanathan, AC, Pasutto, F, Haines, JL, Klaver, CCW, Van Duijn, CM, Casson, RJ, Foster, PJ, Khaw, PT, Hammond, CJ, Mackey, DA, Mitchell, P, Lotery, AJ, Wiggs, JL, Hewitt, AW & Macgregor, S 2020, 'Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression', Nature Genetics, vol. 52, no. 2, pp. 160-166. https://doi.org/10.1038/s41588-019-0556-y

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

In: Nature Genetics, Vol. 52, No. 2, 20.01.2020, p. 160-166.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression

AU - Craig, Jamie E.

AU - Han, Xikun

AU - Qassim, Ayub

AU - Hassall, Mark

AU - Cooke Bailey, Jessica N.

AU - Kinzy, Tyler G.

AU - Khawaja, Anthony P.

AU - An, Jiyuan

AU - Marshall, Henry

AU - Gharahkhani, Puya

AU - Igo, Robert P.

AU - Graham, Stuart L.

AU - Healey, Paul R.

AU - Ong, Jue-sheng

AU - Zhou, Tiger

AU - Siggs, Owen

AU - Law, Matthew H.

AU - Souzeau, Emmanuelle

AU - Ridge, Bronwyn

AU - Hysi, Pirro G.

AU - Burdon, Kathryn P.

AU - Mills, Richard A.

AU - Landers, John

AU - Ruddle, Jonathan B.

AU - Agar, Ashish

AU - Galanopoulos, Anna

AU - White, Andrew J. R.

AU - Willoughby, Colin E.

AU - Andrew, Nicholas H.

AU - Best, Stephen

AU - Vincent, Andrea L.

AU - Goldberg, Ivan

AU - Radford-smith, Graham

AU - Martin, Nicholas G.

AU - Montgomery, Grant W.

AU - Vitart, Veronique

AU - Hoehn, Rene

AU - Wojciechowski, Robert

AU - Jonas, Jost B.

AU - Aung, Tin

AU - Pasquale, Louis R.

AU - Cree, Angela Jane

AU - Sivaprasad, Sobha

AU - Vallabh, Neeru A.

AU - Viswanathan, Ananth C.

AU - Pasutto, Francesca

AU - Haines, Jonathan L.

AU - Klaver, Caroline C. W.

AU - Van Duijn, Cornelia M.

AU - Casson, Robert J.

AU - Foster, Paul J.

AU - Khaw, Peng Tee

AU - Hammond, Christopher J.

AU - Mackey, David A.

AU - Mitchell, Paul

AU - Lotery, Andrew J.

AU - Wiggs, Janey L.

AU - Hewitt, Alex W.

AU - Macgregor, Stuart

PY - 2020/1/20

Y1 - 2020/1/20

N2 - 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.

AB - 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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JO - Nature Genetics

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