Evaluating Practical Approaches for Including MYOC Variants Alongside Common Variants for Genetics-Based Risk...

Area of Science:

• Genetics
• Ophthalmology
• Bioinformatics

Background:

• Rare variants in the MYOC gene are linked to glaucoma risk.
• The p.Gln368Ter variant is the most common pathogenic MYOC variant in Europeans.
• Genetics-based risk stratification can aid in early glaucoma diagnosis.

Purpose of the Study:

• To assess methods for identifying p.Gln368Ter carriers using genotyping array data.
• To evaluate the utility of combining p.Gln368Ter status with polygenic risk scores (PRS) for glaucoma.
• To examine approaches for glaucoma risk stratification.

Main Methods:

• Retrospective cohort study involving 58,452 participants.
• Identification of p.Gln368Ter carriers via direct genotyping and imputation, confirmed with sequencing data.
• Evaluation of combined p.Gln368Ter status and PRS effects.

Main Results:

• p.Gln368Ter can be accurately genotyped with array data and quality control, showing high concordance with sequencing.
• Filtered direct genotyping results agreed well with imputed results.
• Integrating p.Gln368Ter into PRS significantly improved risk stratification for carriers, increasing high-risk classification from ~32-38% to ~75-79%.

Conclusions:

• High-accuracy genotyping of the p.Gln368Ter variant is feasible using array data with proper quality control.
• Incorporating the p.Gln368Ter variant into glaucoma PRS effectively enhances risk stratification for carriers.