The Role of Protein-Coding Variants in South Africans with Exfoliation Glaucoma

Abstract

Purpose: Exfoliation glaucoma (XFG), also called pseudoexfoliation glaucoma, is the most common identifiable form of open-angle glaucoma. Previous genome-wide association studies have identified several genetic risk factors including LOXL1 and CNTNAP2. Our purpose is to examine the role of protein-coding variants in South Africans with XFG.

Methods: Black South African subjects with XFG and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto (Johannesburg, South Africa) and East London Hospital Complex (Eastern Cape, South Africa) using standard clinical examination techniques. We used the Illumina Infinium HumanExome BeadChip containing over 250,000 coding variants to genotype a total of 105 XFG cases and 129 controls. A principal component analysis was performed to address population stratification in these South African samples. We performed the Fisher’s exact test for variants with frequency greater than 0. We also performed logistic regression for all variants with the justification of age and gender for dominant, recessive, and additive models using SAS software.

Results: After quality control and genotype calling, over 71,000 variants were included in the analysis. Principal component analysis indicates that there is no population stratification in these genotyped samples. Our analysis did not identify any association with genome-wide significance (p value < 5 X 10^-8), most probably due to our limited power for detection. For the Fisher’s exact test, the two variants most strongly associated with XFG are rs116243478 in the lysocardiolipin acyltransferase (LCLAT1) gene (p value = 5.4 X 10^-5) and rs113838785 in the dystrotelin (DYTN) gene (p value = 1.1 X 10^-4). Several more promising candidates were also identified using logistic regression analysis with an additive model, including variant rs8078660 in gem-associated protein 4 (GEMIN4) (p value = 2.5 X 10^-4).

Conclusions: We have performed a genome-wide association analysis for exfoliation glaucoma with more than 71,000 variants in a total of 234 South Africans. We did not identify any variants with genome-wide significant association with XFG. Several candidate variants suggest the potential involvement of a number of different genes. It is necessary to replicate our findings in other datasets.

Keywords: 534 gene mapping • 539 genetics • 537 gene screening