Aggregate Effects of Intraocular Pressure and Cup-to-Disc Ratio Genetic Variants on Glaucoma in a Multiethnic Asian Population.

Purpose: High intraocular pressure (IOP) and large vertical cup-to-disc ratio (VCDR) are important risk factors of glaucoma. Recent genome-wide association studies have discovered several genetic variants associated with IOP and VCDR. In this study, we examined the aggregate effects of these IOP-, VCDR-associated variants on glaucoma.

Design: Case-control genetic association study.

Participants: A total of 6881 participants, including 194 glaucoma and 158 primary open-angle glaucoma (POAG) cases in the Singapore Epidemiology of Eye Diseases Study.

Methods: We first identified IOP and VCDR risk single nucleotide polymorphisms (SNPs) that were located in previously discovered IOP, VCDR genetic loci and showed strongest associations with IOP and VCDR in our study. We then constructed multi-locus IOP-, VCDR-specific genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on glaucoma. Associations between tertiles of IOP- and VCDR-specific GRSs with glaucoma and POAG were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under receiver operating characteristic curve (AUC).

Main Outcome Measures: Odds ratios on glaucoma.

Results: Participants in the top tertile of IOP-specific GRS were 2.00 (95% CI, 1.32-3.03, P = 1.1×10(-3)) and 2.50 times (95% CI, 1.54-4.02, P = 2.0×10(-4)) likely to have glaucoma and POAG, respectively, compared with those in the bottom. Participants in the top tertile of VCDR-specific GRS were 2.09 (95% CI, 1.43-3.07, P = 1.6×10(-4)) and 2.31 times (95% CI, 1.50-3.55, P = 1.4×10(-4)) likely to have glaucoma and POAG, respectively. Participants with both GRSs in the top tertile were 5.54 (95% CI, 2.57-11.93, P = 1.1×10(-5)) and 7.77 times (95% CI, 3.03-19.93, P = 2.0×10(-5)) likely to have glaucoma and POAG, respectively, compared with participants with both GRSs in bottom tertiles. The GRSs improved AUC for glaucoma modestly when added to traditional factors (AUC difference = 0.03, P = 0.06).

Conclusions: Higher IOP-, VCDR-specific GRSs were associated with greater risk of glaucoma. Participants with both GRSs in the top tertiles had a 5.5-fold increased risk of glaucoma compared with those in the bottom tertiles. These findings may provide insights into the genetic pathogenesis of glaucoma.