Background
The p.Gln368Ter variant in the MYOC gene is the most important pathogenic variant in glaucoma risk stratification. It can be identified using arrays through direct genotyping or imputation. Yet, there have been concerns regarding the accuracy of genotyping arrays in detecting rare variants, while imputation, which relies on a “black box” algorithm, may be considered unreliable for clinical purposes. Here we explored practical approaches to identifying the p.Gln368Ter variant using array data, and the utility of combining p.Gln368Ter status with polygenic risk scores (PRS) in glaucoma risk stratification.
Methods
We identified p.Gln368Ter carriers using directly genotyped and imputed data for 58452 participants from the Genetics of Glaucoma, QSkin Sun and Health Study (QSKIN), and CARTaGENE projects. Results were confirmed in a subset of 6015 individuals with sequencing data. We evaluated the combined effects of p.Gln368Ter variant and PRS in stratified analyses by considering them as two separate factors and as an aggregate score.
Results
With adequate quality control filtering of individuals for call rate and heterozygosity, the p.Gln368Ter variant could be accurately genotyped in most cases. In 6015 individuals with sequencing data, direct genotyping exhibited perfect concordance with sequencing results. The filtered direct genotyping results showed high agreement with the imputed results, with only 16 discrepancies identified among 57468 individuals. Although p.Gln368Ter status did not affect overall risk prediction in the general population, its incorporation into PRS had additional effects on stratifying high–risk individuals. With the MYOC-enhanced PRS, the proportion of p.Gln368Ter carriers in the top-quartile risk group increased from 32.31% to 75.38% in QSKIN and from 38.24% to 79.41% in CARTaGENE. The MYOC-enhanced PRS correctly placed all p.Gln368Ter carrier glaucoma cases within QSKIN and CARTaGENE in the PRS top-quartile but the original PRS did not.