Zebardast, N;
Sekimitsu, S;
Wang, J;
Elze, T;
Gharahkhani, P;
Cole, BS;
Lin, MM;
... International Glaucoma Genetics Consortium (IGGC); + view all
(2021)
Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank.
Ophthalmology
, 128
(9)
pp. 1300-1311.
10.1016/j.ophtha.2021.03.007.
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Abstract
OBJECTIVE: 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. DESIGN: 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). MAIN OUTCOME MEASURES: 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. CONCLUSION: 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.
| Type: | Article |
|---|---|
| Title: | Characteristics of p.Gln368Ter Myocilin Variant and Influence of Polygenic Risk on Glaucoma Penetrance in the UK Biobank |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ophtha.2021.03.007 |
| Publisher version: | https://doi.org/10.1016/j.ophtha.2021.03.007 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Fundus imaging, Myocilin mutation, Open-angle glaucoma, Penetrance, Polygenic risk score |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10124328 |
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