Phenome-wide association study (PheWAS) using glaucoma-related ocular quantitative traits supports WNT7B association with central corneal thickness

Abstract

Purpose : Connections between the phenome and genome can be identified through phenome wide association studies (PheWAS) where the association between a collection of gene(s) and a wide range of phenotypes are evaluated. For complex traits, such as glaucoma, PheWAS can correlate a disease gene with subphenotypes that may have specific therapies. Previously using 16 consanguineous pedigrees from South India we measured 45 ocular quantitative traits and completed genome-wide association studies and linkage analyses for each trait. Interestingly, in this dataset the top SNP associated with central corneal thickness (CCT) is located within WNT7B, a gene that has been associated with axial length and corneal curvature in a Japanese study. The purpose of this study is to perform a PheWAS for WNT7B SNPs in the South Indian dataset to identify the full range of ocular phenotypes associated with this gene.

Methods : 240 members of 16 consanguineous pedigrees from South India were measured for 45 ocular quantitative traits. Genotyping was performed using the Illumina HumanOmni2.5-8 platform. The top WNT7B SNP (rs10453441) previously associated with axial length and corneal curvature and the top SNP associated with CCT (rs9330813) were selected for PheWAS using all 45 traits. The association tests were performed using likelihood-ratio test in MERLIN after adjusted for age and sex.

Results : After Bonferroni correction (P < 0.001), the top SNP from the Japanese study (rs10453441) was significantly associated with CCT (P = 5.9×10^-4), but not with corneal curvature, axial length or any other quantitative trait. rs9330813, the top SNP associated with CCT in the South Indian study was also significantly associated with CCT in the PheWAS (P = 1.9×10^-7), and was not significantly associated with any other quantitative trait.

Conclusions : The PheWAS results suggest that WNT7B variants are significantly associated only with CCT in the South Indian population. This study also demonstrates the value of PheWAS analyses for evaluating correlations between genes and phenotypes. In future studies this collection of clinical trait associations will provide the detailed phenotype data required for a glaucoma-oriented PheWAS that will be useful for identifying clinical features correlated with genes known to be associated with glaucoma.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.