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Nazlee Zebardast, Sayuri Sekimitsu, Tobias Elze, Jiali Wang, Michael Lin, Brian Cole, Ayellet V Segre, Janey L Wiggs; Penetrance and characteristics of Gln368Ter Myocilin variant in UKBB. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1511.
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MYOC (myocilin) mutations account for 3-5% of primary open angle glaucoma (POAG) and 10-20% of early-onset glaucoma. We aimed to understand the true population-wide penetrance and characteristics of glaucoma among individuals with the most common MYOC variant (p.Gln368Ter) and the impact of a POAG polygenic risk score (PRS) in this population.
We used phenotype and genotype data from the UK Biobank and identified those with p.Gln368Ter variant. POAG PRS was computed based on a large POAG GWAS meta-analysis. Two masked graders reviewed fundus photographs (FPs) for disc-defined glaucoma (DDG).
200 of 73,563 participants with complete data carried the p.Gln368Ter heterozygous genotype and 177 had gradable FPs. 132 had no glaucoma, 45 (25.4%) had probable/definite glaucoma in 1+ eye and 19 (10.7%) had bilateral glaucoma. There were no differences in age, ethnicity, or gender among groups (p>0.05 for all). Of those with DDG, 14 (31%) self-reported or had ICD 9/10 code for glaucoma while 31 (69%) were undiagnosed. Subjects with DDG had higher cornea corrected intraocular pressure (IOPcc) after adjustment for IOP lowering medications (p<0.001) vs. those without DDG. This difference in IOPcc was more pronounced in individuals with DDG with prior glaucoma diagnosis vs. those undiagnosed (p<0.001). The majority of participants with p.Gln368Ter mutation had IOP in the normal range (<=21 mmHg), though this proportion was lower in those with DDG (p<0.02) and those with prior glaucoma diagnosis (p<0.03) (Tab1). The prevalence of DDG increased with each decile of PRS. Subjects with DDG had significantly higher PRS compared to those without glaucoma (1.05 ± 0.60 vs. 0.83 ± 0.56, p=0.03). Of those with DDG, individuals with prior diagnosis of glaucoma had higher PRS compared to undiagnosed individuals (1.63 ± 0.40 vs 0.82 ± 0.50, p<0.001) and had 27.5 (95% CI 2.5-306.6) times adjusted odds of being in the top decile of PRS for POAG (Fig1).
Nearly 1 in 4 individuals with the p.Gln368Ter mutation had evidence of glaucoma, a substantially higher penetrance than previously estimated, with 70% of cases undetected. While IOP plays an important role, a large portion of carriers have IOP in the normal range, despite similar age, including those with DDG. PRS increases disease penetrance and severity of disease, supporting the utility of PRS in optimizing risk stratification among MYOC p.Gln368Ter variant carriers.
This is a 2021 ARVO Annual Meeting abstract.
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