Quantitative traits associated with primary open-angle glaucoma in African ancestry individuals

Abstract

Purpose : We conducted a genome-wide association study (GWAS) on African ancestry individuals, in order to identify genes associated with primary open-angle glaucoma endophenotypes.

Methods : The Primary Open-Angle African American Glaucoma Genetics (POAAGG) study population consists of self-identified Blacks, aged 35 years or older. Quantitative traits were collected on subjects during ophthalmic exams, including intraocular pressure (IOP), cup-to-disc ratio (CDR), central corneal thickness (CCT), visual acuity (VA), retinal nerve fiber layer (RNFL) thickness, mean deviation (MD), and pattern standard deviation (PSD). Genotyping on 5950 subjects including cases and controls was performed using the Multi-Ethnic Genotyping Array V2 (EX) consortium chip. After standard quality control, samples were imputed to the TOPMED phase 3 reference panel using the TOPMED imputation server, which resulted in ~15M variants at R²>0.3 filter. Single variant, quantitative trait association tests were performed using generalized estimating equations (GEE) to account for inter-eye correlation, adjusting for sex and age at study enrollment, with the first five PCs included as fixed effects.

Results : Assuming independence of tests, the genome-wide quantitative trait association studies identified 351 significant SNP-trait associations (p-value<5x10-8) in 107 genomic loci. A total of 6 variants reached genome-wide significance for CDR, as well as 26 variants for baseline IOP, 27 variants IOP max, 99 variants for baseline PSD, 180 variants for MD, 7 variants for RNFL thickness, and 6 variants for VA. SNP association results for central corneal thickness (CCT) did not reach conservative genome-wide significance, assuming independence of all phenotypes evaluated in this study. The SNPs implicated in the associations analysis in our study mapped to genes that include SOX5, CSMD1, EVA1C, PHTF2, EXT1, ACE, CPXM2 and others. In silico and functional validation of the implicated SNPs is currently underway.

Conclusions : Our study recruited, genotyped, and deeply phenotyped the largest-ever cohort of African ancestry individuals with glaucoma from a single city, providing much needed genetic architecture for this most affected population. Glaucoma is an inherently complex and heterogenous disease, making this deep phenotyping necessary for understanding the pathophysiology of disease and to study the influence of genetic variations.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.