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Purpose: This study aimed to develop and validate a comprehensive polygenic risk score (PRS) for keratoconus, enhancing the predictive accuracy for identifying individuals at increased risk, which is crucial for preventing keratoconus-associated visual impairment such as post-Laser-assisted in situ keratomileusis (LASIK) ectasia., Methods: We applied a multi-trait analysis approach (MTAG) to genome-wide association study data on keratoconus and quantitative keratoconus-related traits and used this to construct PRS models for keratoconus risk using several PRS methodologies. We evaluated the predictive performance of the PRSs in two biobanks: Estonian Biobank (EstBB; 375 keratoconus cases and 17 902 controls) and UK Biobank (UKB: 34 keratoconus cases and 1000 controls). Scores were compared using the area under the curve (AUC) and odds ratios (ORs) for various PRS models., Results: The PRS models demonstrated significant predictive capabilities in EstBB, with the SBayesRC model achieving the highest OR of 2.28 per standard deviation increase in PRS, with a model containing age, sex and PRS showing good predictive accuracy (AUC = 0.72). In UKB, we found that adding the best-performing PRS to a model containing corneal measurements increased the AUC from 0.84 to 0.88 (P = 0.012 for difference), with an OR of 4.26 per standard deviation increase in the PRS. These models showed improved predictive capability compared to previous keratoconus PRS., Conclusion: The PRS models enhanced prediction of keratoconus risk, even with corneal measurements, showing potential for clinical use to identify individuals at high risk of keratoconus, and potentially help reduce the risk of post-LASIK ectasia., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)