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An intraocular pressure polygenic risk score stratifies multiple primary open angle glaucoma parameters including treatment intensity

An intraocular pressure polygenic risk score stratifies multiple primary open angle glaucoma parameters including treatment intensity
An intraocular pressure polygenic risk score stratifies multiple primary open angle glaucoma parameters including treatment intensity
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.
0161-6420
901-907
Qassim, Ayub
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Lotery, Andrew
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Siggs, Owen
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Hassall, Mark
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Han, Xikun
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Griffiths, Helen
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Frost, Andrew
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Vallabh, Neeru
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Kirwan, James F.
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Menon, Geeta
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Cree, Angela J.
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Galanopoulos, Anna
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Agar, Ashish
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Graham, Stuart
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Landers, John
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Casson, Robert
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Willoughby, Colin E.
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Hewitt, Alex W.
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Macgregor, Stuart
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Craig, Jamie E.
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Qassim, Ayub
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Lotery, Andrew
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Siggs, Owen
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Hassall, Mark
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Han, Xikun
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Griffiths, Helen
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Frost, Andrew
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Cree, Angela J.
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Healey, Paul
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Graham, Stuart
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Landers, John
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Casson, Robert
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Gharahkhani, Puya
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Willoughby, Colin E.
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Hewitt, Alex W.
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Macgregor, Stuart
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Craig, Jamie E.
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Qassim, Ayub, Lotery, Andrew, Souzeau, Emmanuelle, Siggs, Owen, Hassall, Mark, Han, Xikun, Griffiths, Helen, Frost, Andrew, Vallabh, Neeru, Kirwan, James F., Menon, Geeta, Cree, Angela J., Galanopoulos, Anna, Agar, Ashish, Healey, Paul, Graham, Stuart, Landers, John, Casson, Robert, Gharahkhani, Puya, Willoughby, Colin E., Hewitt, Alex W., Macgregor, Stuart and Craig, Jamie E. (2020) An intraocular pressure polygenic risk score stratifies multiple primary open angle glaucoma parameters including treatment intensity. Ophthalmology, 127 (7), 901-907. (doi:10.1016/j.ophtha.2019.12.025).

Record type: Article

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.

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Accepted/In Press date: 20 December 2019
e-pub ahead of print date: 6 January 2020
Published date: July 2020

Identifiers

Local EPrints ID: 439365
URI: http://eprints.soton.ac.uk/id/eprint/439365
ISSN: 0161-6420
PURE UUID: 3b7635e6-6f2e-45b5-80a1-30880d4df449
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 17 Apr 2020 16:35
Last modified: 22 Nov 2021 08:06

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Contributors

Author: Ayub Qassim
Author: Andrew Lotery ORCID iD
Author: Emmanuelle Souzeau
Author: Owen Siggs
Author: Mark Hassall
Author: Xikun Han
Author: Helen Griffiths
Author: Andrew Frost
Author: Neeru Vallabh
Author: James F. Kirwan
Author: Geeta Menon
Author: Angela J. Cree
Author: Anna Galanopoulos
Author: Ashish Agar
Author: Paul Healey
Author: Stuart Graham
Author: John Landers
Author: Robert Casson
Author: Puya Gharahkhani
Author: Colin E. Willoughby
Author: Alex W. Hewitt
Author: Stuart Macgregor
Author: Jamie E. Craig

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