Genome-wide association study of corneal dystrophy uncovers novel risk loci and enables improved polygenic prediction of Fuchs endothelial corneal dystrophy.

Objective: To identify risk loci for Fuchs endothelial corneal dystrophy (FECD) and improve a genetic risk prediction model. Design: Genome-wide association study (GWAS), polygenic risk score (PRS) construction, and TCF4 CTG18.1 short tandem repeat (STR) length inference. Participants: The study included 7,316 Europeans (EUR) with FECD or related corneal dystrophy phenotypes and 1,588,467 controls from the UK Biobank, All of Us, FinnGen, and the Million Veteran Program. Two independent EUR FECD cohorts were used for PRS validation (1,851/2,679 cases/controls and 124/257 cases/controls). African (AFR) ancestry analyses included 455 cases and 121,154 controls to build PRS. A subset of All of Us participants was used for joint PRS and STR modelling. Methods: GWAS meta-analyses were performed using FECD diagnoses or corneal dystrophy proxies where necessary, with validity assessed via genetic correlation. Risk loci were identified, and ancestry-specific PRSs were constructed using SBayesRC. PRS performance was evaluated across ancestries with and without TCF4 STR data. Main Outcome: We identified novel loci for corneal dystrophy and constructed PRS-based and STR-based prediction models. Results: The GWAS meta-analysis identified 24 risk loci associated with corneal dystrophy, including 12 novel loci, doubling previous FECD studies. The optimised PRS outperformed existing models in two independent FECD validation cohorts (AUC = 0.83, 95% CI: 0.82-0.84; DeLong's Conclusions: These findings refine the genetic architecture of FECD, enhance risk prediction, and support a tiered strategy integrating STR expansion testing with PRS.