What is the association of monogenic and polygenic variants with glaucoma risk?
In this cross-sectional study of 2507 individuals with open-angle glaucoma, high polygenic risk was associated with risk of developing glaucoma comparable with the risk associated with the most common single-gene pathogenic variant, but was more than 15 times more prevalent in the general population than this single-gene variant.
In this study, polygenic variants were associated with a comparable risk of developing glaucoma as some monogenic risk variants and were more prevalent in the general population.
Early diagnosis of open-angle glaucoma can lead to vision-saving treatment, and genetic variation is an increasingly powerful indicator in disease risk stratification.
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.
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.
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Siggs OM, Han X, Qassim A, et al. Association of Monogenic and Polygenic Risk With the Prevalence of Open-Angle Glaucoma. JAMA Ophthalmol. Published online July 15, 2021. doi:10.1001/jamaophthalmol.2021.2440
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