Keratoconus May Be Identified With Genetic Variants, Report Shows

topography of the cornea with an unpleasant diagnosis of keratoconus stage 2-3
Monitoring corneal resistance factor and central corneal thickness may improve polygenic risk score models for the common corneal ectasia.

Novel genetic variants are associated with corneal resistance factor (CRF) and central corneal thickness (CCT), according to a study published in JAMA Ophthalmology. The study shows that a polygenic risk score model for keratoconus susceptibility may accurately identify cases of keratoconus by testing for the CRF- or CCT-associated variants.

To identify novel genetic variants for keratoconus, the researchers used CRF and CCT as quantitative corneal traits to conduct a multitrait genome-wide association study (GWAS). 

For the GWAS, the researchers used CRF data from participants of European ancestry in the UK Biobank (UKB) (n=105,427) and the Canadian Longitudinal Study on Aging (CLSA) (n=18,307) and summary statistics of a CCT GWAS meta-analysis of participants of European ancestry in the International Glaucoma Genetics Consortium (IGGC) (n=17,803). They then used self-reported race and ethnicity to replicate the analyses using UKB and CLSA data of participants with South and East Asian ancestry. The team also compared their results with CRF and CCT variants in published keratoconus datasets (4669 cases and 116,547 controls). 

The CRF GWAS included data from participants comprising 4 cohorts: 105,427 UKB European ancestry (53% women and 47% men; mean age 57±8 years), 5029 UKB South Asian ancestry (47% women and 53% men; mean age 54±8 years), 902 UKB East Asian ancestry (69% women and 31% men; mean age 53±8 years), and 18,307 CLSA European ancestry (51% women and 49% men; mean age 63±10 years). 

The researchers identified 369 variants associated with CRF, 36 of which were novel associations, and 233 variants associated with CCT, including 114 novel associations. Of these, 29 of the CRF-associated variants and 24 of the CCT-associated variants were associated with keratoconus. 

The team then constructed polygenic risk scores (PRS) using the CRF- and CCT-associated variants and published keratoconus variants. They found that adding a CRF- or CCT-based PRS to the keratoconus PRS based on the previously published variants improved the prediction area under the receiver-operating characteristic curve (from 0.705 to 0.756 for CRF and from 0.715 to 0.755 for CCT).

“These findings support the use of multitrait modeling of corneal parameters in a relatively large data set to identify new keratoconus risk loci and enhance polygenic risk score models,” the researchers explain.

Limitations of the study included incomplete replication of the GWAS findings in the Asian populations, which was potentially due to low statistical power, and there was an overlap (2%) between the UKB dataset used to test the PRS model and the previously published keratoconus meta-analysis.


He W, Han X, Ong JS, et al. Association of novel loci with keratoconus susceptibility in a multitrait genome-wide association study of the UK biobank database and Canadian longitudinal study on aging. JAMA Ophthalmol. Published online April 20, 2022. doi:10.1001/jamaophthalmol.2022.0891