Ocular phenome-wide association study (PheWAS) of glaucoma-associated genes identifies significant associations with ocular quantitative traits

Abstract

Purpose : Phenome wide association studies (PheWAS) can correlate a disease gene with subphenotypes that may provide insights into relevant disease mechanisms that could suggest novel therapies. A number of genes have been associated with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in previous genome-wide association studies (GWAS). Previously we measured 45 ocular quantitative traits in 15 consanguineous pedigrees from South India and completed GWAS and linkage analyses for each trait. The purpose of this study is to perform an ocular PheWAS for POAG and PACG associated genes in the South Indian dataset to identify the full range of ocular phenotypes associated with these genes.

Methods : 195 individuals of 15 consanguineous pedigrees from South India were measured for 45 ocular quantitative traits. Genotyping was performed using the Illumina HumanOmni2.5-8 platform. The top SNPs or proxy SNPs of 15 POAG-associated genes and 9 PACG-associated genes previously identified from GWAS were selected for PheWAS. The association tests were performed using likelihood-ratio test in MERLIN after adjusted for age and sex.

Results : Of 45 ocular quantitative traits, 17 traits were selected for PheWAS. The other 28 traits were excluded from PheWAS due to either high correlation (|r| > 0.2) or insufficient statistical power to detect the association (< 80% of power). The PheWAS identified interesting associations of 10 POAG-associated genes and 5 PACG-associated genes with a range of ocular quantitative traits (P < 0.05). Two of these associations (ABCA1 with retinal nerve fiber layer thickness, and chr8q22 with corneal hysteresis) remained significant after Bonferroni correction (P < 0.003).

Conclusions : The PheWAS results suggest that glaucoma-associated genes are associated with a variety of glaucoma subphenotypes in the South Indian population. Additional studies in other ethnic populations are required to confirm these associations. These results provide new information about the role of POAG and PACG genes in disease development that could lead to novel gene-based therapies for these common forms of glaucoma.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.