Lightning Talk GENEMAPPERS 2026

Genome-wide association study of corneal dystrophy uncovers novel risk loci and enables improved polygenic prediction of Fuchs endothelial corneal dystrophy (#10)

Benyapa Insawang 1 2 , David A Mackey 3 , Alex W Hewitt 3 4 , Jamie E Craig 5 , Richard Mills 5 , Puya Gharahkhani 6 , Stuart MacGregor 1
  1. Statistical Genetics Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  2. Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
  3. Centre for Ophthalmology and Visual Science, University of Western Australia, Lions Eye Institute, Perth, WA, Australia
  4. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  5. Department of Ophthalmology, Flinders Health and Medical Research Institute, Flinders University, Adelaide, South Australia, Australia
  6. Queensland Institute of Medical Research Berghofer Medical Research Institute, Faculty of Medicine, University of Queensland, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia

Fuchs endothelial corneal dystrophy (FECD) is a progressive, hereditary eye disorder and the leading indication for corneal transplantation worldwide. With no available cure, early identification of individuals at risk is critical to prevent irreversible corneal damage and guide clinical decisions. Current predictive models for FECD exhibit limited accuracy, and improving our understanding of its genetic contributors may help improve risk stratification. To address this, we performed a large-scale genome-wide association study (GWAS) meta-analysis across four major cohorts: the UK Biobank, All of Us, FinnGen, and the Million Veteran Program, comprising 7,316 patients and 1,588,467 controls of European ancestry. Because FECD-specific diagnostic codes were not consistently available, we analysed FECD and, when necessary, used the broader hereditary corneal dystrophy as proxy phenotypes, validating this approach through genetic correlation testing. We developed a polygenic risk score (PRS) and used two FECD-specific independent cohorts for validation (1,851 cases and 2,679 controls; 124 cases and 257 controls). Our analysis identified 24 genetic risk loci relevant to corneal dystrophy, doubling the previously reported number for FECD, including 12 novel loci, many of which overlap with genes associated with other eye traits. Leveraging SBayesRC, we developed an optimised PRS that outperformed existing models in predictive accuracy. Our PRS achieved an AUC of 0.82 (95% CI: 0.81–0.84), significantly exceeding the published PRS (DeLong’s test P = 8.03 × 10-13). In independent validation cohorts, individuals within the top decile of the PRS distribution exhibited markedly higher disease risk: 13-fold (95% CI: 10–17) in cohort 1 and 19-fold (95% CI: 8–57) in cohort 2, relative to the remainder. These discoveries not only broaden the genetic landscape of FECD but also highlight the transformative potential of advanced PRS for early risk stratification, setting the stage for precision-driven screening, surgical planning, and potential integration into routine ophthalmic care.