Rare Genetic Variants are Associated with POAG in Populations of African Ancestry

Abstract

Purpose: Individuals of African Ancestry are 4-5 times more likely to develop primary open angle glaucoma (POAG) than Caucasians, but little is known about their genetic risk factors. We evaluate the association of rare genetic variants to POAG in African Americans and a population from Ghana, West Africa.

Methods: The Illumina HumanExome BeadChip containing over 250,000 variants was used to genotype 2834 individuals of African Ancestry: African Americans (666 POAG cases and 668 controls) and Ghanaians (750 POAG cases, 750 controls). Principle component analysis (PCA) of 1800 ancestry informative markers on the BeadChip was used to identify population stratification. Rare variants were analyzed for association with POAG, using both single variant and gene collapsing tests implemented in Plink-Seq

Results: PCA indicated that African Americans in this dataset are genetically derived from admixture between the parental West African (Ghanaian) and Caucasian populations. A variant in the TMCO4 gene was found to be associated in African Americans with both Fisher’s Exact Test (p=3.6x10-5; OR=0.43) and the c alpha test (p=9x10-6). The role of TMCO4 is unknown; but a closely-related gene, TMCO1, has been associated with POAG in Caucasians. Fisher’s Exact Test also shows that a variant in TMCO4 is associated in the Ghanaian dataset (p= 7.7x10-3). Two more genes among the 10 strongest associations in the African American exome chip analysis were replicated in the Ghanaian dataset. ACSL5 is associated in African Americans (p=8x10-5; OR=0.33), and this gene replicates in the Ghanaian dataset (p=0.01; OR=0.11); and intergenic SNPs near THSD7B are associated in both African Americans (p=1x10-4; OR=0.62) and Ghanaians (p=0.01; OR=0.18). Both of these genes are expressed in the retina. Full meta-analysis of all 2834 samples in both datasets will be presented.

Conclusions: We have identified multiple genes associated with POAG pathogenesis in both African Americans and Ghanaians. TMCO4 is closely related to TMCO1, which has previously been associated with POAG in Caucasians, and may affect apoptotic cell death. THSD7B belongs to a large family of genes containing thrombospondin type 1 domains, including ADMSTS10, a gene responsible for glaucoma in dogs, as well as a syndromic form of glaucoma in a Lebanese family. Future directions include sequencing of selected candidate genes and functional analysis of the variants identified.

Keywords: 539 genetics