Integrating corneal endophenotypes with classic GWAS approaches identifies novel keratoconus loci

Keratoconus is a chronic progressive disorder characterized by corneal deformation. It usually affects adolescents and young adults, reducing vision and decreasing the quality of life. Here we show that integrating genetic analyses of corneal traits with large case-control studies improves the discovery and annotation of genetic factors underlying keratoconus. Analysing corneal imaging measurements from 16,464 individuals, we identify four informative corneal traits and use them in a multi-trait genetic analysis that uncovers 80 significant loci associated with one or more of the selected traits. Twenty-five of these loci (5 novel) are also associated with keratoconus (Bonferroni-corrected P ≤ 6.3 × 10 −4 ). A subsequent meta-analysis of 6,372 cases and 593,541 controls identifies 51 significant keratoconus loci ( P ≤ 5.0 × 10 −8 ), including eight not previously reported. Gene-set analysis implicates pathways involved in extracellular matrix integrity, glucosylceramidase regulation and cellular differentiation. These findings expand the genetic landscape of keratoconus, provide insight into the biological mechanisms underlying disease development, and support future efforts in genetic risk profiling and therapeutic target discovery.