Rare Genetic Variants in African Americans with Primary Open Angle Glaucoma

Abstract

Purpose: African Americans are 4 times more likely to develop primary open angle glaucoma (POAG) than Caucasians, but little is known about their genetic risk factors. In contrast, genome wide association studies (GWAS) have successfully identified several POAG risk genes in Caucasians including CAV1/2, CDKN2BAS, TMCO1, SIX1/SIX6, and an intergenic region on 8p22. We have reported that these common susceptibility alleles in Caucasians were not associated with POAG in African Americans (Allingham et al, ARVO, 2012). Here, we evaluate whether rare variants in these or other genes contribute to POAG risk in African Americans.

Methods: The Illumina Infinium HumanExome BeadChip containing over 250,000 variants was genotyped in 666 POAG cases and 668 controls. Principle component analysis of ancestry informative markers on the Beadchip was used to identify population stratification. Rare variant association tests which collapse variants by gene were performed using Plink-Seq.

Results: 130,402 SNPs were polymorphic and after excluding common (>5%) and non-coding variants, 94,240 SNPs remained available for analysis. Known Caucasian POAG loci had marginal coverage on the chip, preventing an analysis of rare variants in African Americans. Five genes with rare variants demonstrated marginal association with POAG in our data set. These were Ewing tumor-associated antigen 1 (ETAA1; p=5x10-6 variable threshold test; p=6x10-6 burden test), aminoglycoside phosphotransferase domain-containing protein 1 (AGPHD1; p=9x10-6 C-alpha test), transmembrane and coiled-coil domain 4 (TMCO4; p=9x10-6 calpha test), synuclein-alpha interacting protein (SNCAIP; p=0.0001 variable threshold test; p=3x10-5 burden test) and polyhomeotic-like 2 (PHC2; p=1x10-5 variable threshold test; p=2x10-5 burden test).

Conclusions: We have identified multiple biologic pathways associated with POAG pathogenesis in both African Americans and Caucasians. Although we could not evaluate TMCO1, we identified support for TMCO4 in African American POAG risk. Our results also implicate the ubiquitination pathway in POAG etiology. PHC2 is part of the polycomb group of genes and believed to be involved in histone ubiquitination. CDKN2BAS, identified in Caucasian POAG, is also part of the ubiquitination pathway. Future directions include performing rare variant imputation, sequencing of selected candidate genes, and performing a GWAS with common variants.

Keywords: 539 genetics