Integrated monogenic and polygenic risk predicts disease progression in Fuchs endothelial corneal dystrophy

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Abstract Purpose Fuchs endothelial corneal dystrophy (FECD) is a common corneal disease and a leading indication for endothelial keratoplasty (EK). Although CTG18.1 repeat expansion is a major genetic risk factor, the contribution of polygenic background to disease progression remains unclear. We evaluated whether combining CTG18.1 expansion status with a FECD-specific polygenic risk score (PRS) enables genomic prediction of progression to EK. Methods We retrospectively analysed 589 individuals with FECD from two European centers, with replication in an independent cohort of 185 individuals. Association of CTG18.1 expansion (≥50 repeats) and PRS with time to EK were evaluated using Cox models adjusted for sex and ancestry. Results Expansion-positive status was associated with earlier EK (HR 2.30; 95% CI 1.62– 3.26; P<.001). Addition of PRS improved prediction (C-index 0.614 vs 0.602; P=.014). Each 1-SD increase in PRS was associated with earlier EK (HR 1.16; 95% CI 1.03–1.30; P=.015), with replication in the validation cohort (HR 1.42; 95% CI 1.15–1.75; P=.001). Conclusion Integration of monogenic and polygenic risk enables genomic prediction of FECD progression, supporting clinical genomic risk stratification to inform individualized monitoring and timing of intervention.

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