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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.

Titel:	Multitrait analysis of glaucoma identifies new risk loci and enables polygenic prediction of disease susceptibility and progression.
Autor/in / Beteiligte Person:	Craig, JE ; Han, X ; Qassim, A ; Hassall, M ; Cooke Bailey, JN ; Kinzy, TG ; Khawaja, AP ; An, J ; Marshall, H ; Gharahkhani, P ; Igo RP Jr ; Graham, SL ; Healey, PR ; Ong, JS ; 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
Link:	View record at Springer (Volltext)
Zeitschrift:	Nature genetics, Jg. 52 (2020-02-01), Heft 2, S. 160-166
Veröffentlichung:	New York, NY : Nature Pub. Co., c1992-, 2020
Medientyp:	academicJournal
ISSN:	1546-1718 (electronic)
DOI:	10.1038/s41588-019-0556-y
Schlagwort:	Australia Case-Control Studies Cytoskeletal Proteins genetics Disease Progression Eye Proteins genetics Genetic Predisposition to Disease Genome-Wide Association Study Glaucoma etiology Glaucoma surgery Glycoproteins genetics Humans Intraocular Pressure genetics Multifactorial Inheritance Odds Ratio Optic Nerve physiology Penetrance Trabeculectomy adverse effects United Kingdom United States Glaucoma genetics Polymorphism, Single Nucleotide
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Corporate Authors: NEIGHBORHOOD consortium ; UK Biobank Eye and Vision Consortium Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Nat Genet] 2020 Feb; Vol. 52 (2), pp. 160-166. <i>Date of Electronic Publication: </i>2020 Jan 20. MeSH Terms: Polymorphism, Single Nucleotide* ; Glaucoma / *genetics ; Australia ; Case-Control Studies ; Cytoskeletal Proteins / genetics ; Disease Progression ; Eye Proteins / genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Glaucoma / etiology ; Glaucoma / surgery ; Glycoproteins / genetics ; Humans ; Intraocular Pressure / genetics ; Multifactorial Inheritance ; Odds Ratio ; Optic Nerve / physiology ; Penetrance ; Trabeculectomy / adverse effects ; United Kingdom ; United States References: Weinreb, R. N. & Khaw, P. T. Primary open-angle glaucoma. Lancet 363, 1711–1720 (2004). 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Grant Information: MC_PC_12028 United Kingdom MRC_ Medical Research Council; MC_PC_17228 United Kingdom MRC_ Medical Research Council; U01 HG004728 United States HG NHGRI NIH HHS; R21 EY028671 United States EY NEI NIH HHS; MR/T040912/1 United Kingdom MRC_ Medical Research Council; R01 EY022305 United States EY NEI NIH HHS; R01 EY015473 United States EY NEI NIH HHS; MC_UU_00007/10 United Kingdom MRC_ Medical Research Council; P30 EY031631 United States EY NEI NIH HHS; MC_QA137853 United Kingdom MRC_ Medical Research Council Substance Nomenclature: 0 (Cytoskeletal Proteins) ; 0 (Eye Proteins) ; 0 (Glycoproteins) ; 0 (trabecular meshwork-induced glucocorticoid response protein) Entry Date(s): Date Created: 20200122 Date Completed: 20200413 Latest Revision: 20220302 Update Code: 20240513 PubMed Central ID: PMC8056672

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