Ayub Qassim1, Emmanuelle Souzeau2, Owen M Siggs2, Mark M Hassall2, Xikun Han3, Helen L Griffiths4, N Andrew Frost5, Neeru A Vallabh6, James F Kirwan7, Geeta Menon8, Angela J Cree4, Anna Galanopoulos9, Ashish Agar10, Paul R Healey11, Stuart L Graham12, John Landers2, Robert J Casson13, Puya Gharahkhani3, Colin E Willoughby14, Alex W Hewitt15, Andrew J Lotery4, Stuart MacGregor3, Jamie E Craig2. 1. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia. Electronic address: ayub.qassim@flinders.edu.au. 2. Department of Ophthalmology, Flinders University, Flinders Medical Centre, Bedford Park, Australia. 3. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 4. Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. 5. Department of Ophthalmology, Torbay Hospital, Torquay, Devon, United Kingdom. 6. Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom. 7. Department of Ophthalmology, Portsmouth Hospitals, Portsmouth, United Kingdom. 8. Department of Ophthalmology, Frimley Park Hospital NHS Foundation Trust, Frimley, United Kingdom. 9. South Australian Institute of Ophthalmology, Royal Adelaide Hospital, Adelaide, Australia. 10. Department of Ophthalmology, Prince of Wales Hospital, Randwick, Australia. 11. Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia. 12. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia. 13. South Australian Institute of Ophthalmology, University of Adelaide, Adelaide, Australia. 14. Biomedical Sciences Research Institute, Ulster University, Coleraine, United Kingdom; Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom. 15. Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.
Abstract
PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.
PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification. DESIGN: Cross-sectional study. PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients. METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group. MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity. RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01). CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucomapatients and their close family members.
Authors: Manoel Vinicius Rocha Araki; Yuri Carvalho Oiamore Silva; Thiago Adalton Rosa Rodrigues; Flavia Fialho Bajano; Bruno Batista de Souza; Fernando Ferreira Costa; Vital Paulino Costa; Mônica Barbosa de Melo; José Paulo Cabral de Vasconcellos Journal: Mol Vis Date: 2022-02-22 Impact factor: 2.367
Authors: Ryan Zukerman; Alon Harris; Alice Verticchio Vercellin; Brent Siesky; Louis R Pasquale; Thomas A Ciulla Journal: Genes (Basel) Date: 2020-12-31 Impact factor: 4.096