The University of Southampton
University of Southampton Institutional Repository

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
3a3f5773-01ba-4fe5-addc-ece7b2058330
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Souzeau, Emmanuelle
005c82f2-d220-4995-b722-bab94749eb9b
Siggs, Owen
ab7d0e36-bd76-4def-9c61-fed63335477d
Hassall, Mark
289a5633-4595-483c-87fb-fcc606790b36
Han, Xikun
fc4c3b7e-bf6d-4c6f-b178-def18c321ad6
Griffiths, Helen
a097fdaa-d3d6-49a9-9c69-0e6e5a5d518b
Frost, Andrew
88419236-9f51-4865-b763-2876ab095ec3
Vallabh, Neeru
9b8ab614-9059-439e-98d4-448786a976fa
Kirwan, James F.
8cf3e23f-cd72-47af-a94c-3aee70b8d206
Menon, Geeta
941f77e0-5d93-49a8-ac38-a250c4bdbc06
Cree, Angela J.
609d60f6-7d1c-4ad0-a8df-81156bea8339
Galanopoulos, Anna
621e11a3-8217-4fef-96c8-a270d273e0f6
Agar, Ashish
7874c2d2-6152-445b-8125-14a00cf02e72
Healey, Paul
ac1f652e-1458-4062-878e-3aba876a2c74
Graham, Stuart
45346713-fb0c-4f4e-99ff-13a01b91577e
Landers, John
29da3a55-c26a-4beb-9686-e577bdf43521
Casson, Robert
4bfa027c-2e57-4ac5-8a8f-f7b8ae1e9abc
Gharahkhani, Puya
92bfede3-a0fa-47cf-85f2-451499a6a746
Willoughby, Colin E.
ddcffa2c-54a1-4fc8-9106-873dc00c707e
Hewitt, Alex W.
9dffa147-6f00-40df-9f18-95f8552aa140
Macgregor, Stuart
906f8ca2-d3d1-46fe-ad87-bc016280aefe
Craig, Jamie E.
795b9c1d-b781-4a27-90ce-cd0ddaa70a9a
Qassim, Ayub
3a3f5773-01ba-4fe5-addc-ece7b2058330
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Souzeau, Emmanuelle
005c82f2-d220-4995-b722-bab94749eb9b
Siggs, Owen
ab7d0e36-bd76-4def-9c61-fed63335477d
Hassall, Mark
289a5633-4595-483c-87fb-fcc606790b36
Han, Xikun
fc4c3b7e-bf6d-4c6f-b178-def18c321ad6
Griffiths, Helen
a097fdaa-d3d6-49a9-9c69-0e6e5a5d518b
Frost, Andrew
88419236-9f51-4865-b763-2876ab095ec3
Vallabh, Neeru
9b8ab614-9059-439e-98d4-448786a976fa
Kirwan, James F.
8cf3e23f-cd72-47af-a94c-3aee70b8d206
Menon, Geeta
941f77e0-5d93-49a8-ac38-a250c4bdbc06
Cree, Angela J.
609d60f6-7d1c-4ad0-a8df-81156bea8339
Galanopoulos, Anna
621e11a3-8217-4fef-96c8-a270d273e0f6
Agar, Ashish
7874c2d2-6152-445b-8125-14a00cf02e72
Healey, Paul
ac1f652e-1458-4062-878e-3aba876a2c74
Graham, Stuart
45346713-fb0c-4f4e-99ff-13a01b91577e
Landers, John
29da3a55-c26a-4beb-9686-e577bdf43521
Casson, Robert
4bfa027c-2e57-4ac5-8a8f-f7b8ae1e9abc
Gharahkhani, Puya
92bfede3-a0fa-47cf-85f2-451499a6a746
Willoughby, Colin E.
ddcffa2c-54a1-4fc8-9106-873dc00c707e
Hewitt, Alex W.
9dffa147-6f00-40df-9f18-95f8552aa140
Macgregor, Stuart
906f8ca2-d3d1-46fe-ad87-bc016280aefe
Craig, Jamie E.
795b9c1d-b781-4a27-90ce-cd0ddaa70a9a

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.

Text
Tracked changes[1967192] - Accepted Manuscript
Download (28kB)

More information

Accepted/In Press date: 20 December 2019
e-pub ahead of print date: 6 January 2020
Published date: 1 July 2020
Additional Information: Funding Information: Supported by the National Health and Medical Research Council of Australia (grant nos.: 1107098, 1116360, 1116495, and 1023911; fellowships to S.M., J.E.C., and A.W.H.); the Ophthalmic Research Institute of Australia; the BrightFocus Foundation; the International Glaucoma Association; the UK and Eire Glaucoma Society; and the Mason Medical Research Foundation. The funding organizations had no role in the design or conduct of this research. Publisher Copyright: © 2020 American Academy of Ophthalmology

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

Catalogue record

Date deposited: 17 Apr 2020 16:35
Last modified: 17 Mar 2024 05:12

Export record

Altmetrics

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×