MYOC (myocilin) mutations account for 3-5% of primary open angle glaucoma (POAG). 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.
Cross-sectional population-based METHODS: Individuals with the p.Gln368Ter variant were identified among 77,959 UK Biobank participants with fundus photographs (FPs). A genome-wide POAG PRS was computed and two masked graders reviewed FPs for disc-defined glaucoma (DDG).
Penetrance of glaucoma RESULTS: 200 individuals carried the p.Gln368Ter heterozygous genotype, and 177 had gradable FPs. 132 had no evidence of glaucoma, 45 (25.4%) had probable/definite glaucoma in at least one eye and 19 (10.7%) had bilateral glaucoma. There were no differences in age, race/ethnicity, or gender among groups (p>0.05). Of those with DDG, 31% self-reported or had ICD 9/10 code for glaucoma, while 69% were undiagnosed. Subjects with DDG had higher medication-adjusted cornea-corrected intraocular pressure (IOPcc) (p<0.001) vs. those without glaucoma. This difference in IOPcc was larger in DDG with prior glaucoma diagnosis vs. those not diagnosed (p<0.001). Majority of p.Gln368Ter carriers 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). Prevalence of DDG increased with each decile of the POAG PRS. Subjects with DDG had significantly higher PRS compared to those without glaucoma (0.37 ± 0.97 vs 0.01 ± 0.90, p=0.03). Of those with DDG, individuals with prior diagnosis of glaucoma had higher PRS compared to undiagnosed individuals (1.31 ± 0.64 vs 0.00 ± 0.81, p<0.001) and had 27.5 times (95%CI 2.5-306.6) adjusted odds of being in the top decile of PRS for POAG.
1 in 4 individuals with MYOC p.Gln368Ter mutation had evidence of glaucoma, a substantially higher penetrance than previously estimated, with 69% of cases undetected. A large portion of p.Gln368Ter 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 carriers.

Copyright © 2021. Published by Elsevier Inc.