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Association of monogenic and polygenic risk with the prevalence of open-angle glaucoma

journal contribution
posted on 2023-05-21, 03:29 authored by Siggs, OM, Han, X, Qassim, A, Souzeau, E, Kuruvilla, S, Marshall, HN, Mullany, S, David MackeyDavid Mackey, Alexander HewittAlexander Hewitt, Gharahkhani, P, MacGregor, S, Craig, JE

Importance: Early diagnosis of open-angle glaucoma can lead to vision-saving treatment, and genetic variation is an increasingly powerful indicator in disease risk stratification.

Objective: To compare polygenic and monogenic variants in risk of glaucoma.

Design, setting, and participants: Clinical and genetic data were obtained for 2507 individuals from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) and 411 337 individuals in cross-sectional cohort studies including individuals of European ancestry in the UK Biobank. Recruitment to the UK Biobank occurred between 2006 and 2010, and data analysis occurred between September 2019 and August 2020.

Main outcomes and measures: Association of monogenic and polygenic variants with glaucoma risk.

Results: Individuals at high polygenic risk, defined as those in the top 5% of an unselected population, had a glaucoma risk (odds ratio [OR], 2.77; 95% CI, 2.58-2.98) comparable with the risk among individuals heterozygous for the MYOC p.Gln368Ter variant (OR 4.19; 95% CI, 3.25-5.31), which is the most common single-gene variant known to cause primary open-angle glaucoma. High polygenic risk was more than 6 times more common than MYOC p.Gln368Ter heterozygosity in ANZRAG (15.7% vs 2.6%) and more than 15 times more common in the general population (5.0% vs 0.32%). Within ANZRAG, high polygenic risk was associated with a mean (SD) age at glaucoma diagnosis that did not differ from the age at glaucoma diagnosis among individuals heterozygous for MYOC p.Gln368Ter (57.2 [14.2] vs 54.8 [13.6] years; P > .99).

Conclusions and relevance: Monogenic and high polygenic risk were each associated with a more than 2.5-fold increased odds of developing glaucoma and an equivalent mean age at glaucoma diagnosis, with high polygenic risk more than 15 times more common in the general population.

History

Publication title

JAMA Ophthalmology

Volume

139

Issue

9

Pagination

1023-1028

ISSN

2168-6165

Department/School

Tasmanian School of Medicine

Publisher

American Medical Association

Place of publication

United States

Rights statement

Copyright 2021 American Medical Association

Repository Status

  • Restricted

Socio-economic Objectives

Diagnosis of human diseases and conditions

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