Genome-wide association study of primary open-angle glaucoma in continental and admixed African populations.

Abstract

Purpose : Primary open-angle glaucoma (POAG) is the predominant type of glaucoma worldwide. Its prevalence varies greatly among ethnic groups, and is the highest in Black African populations (2-7%). So far worldwide efforts to elucidate the genetic complexity of POAG in African populations has been very limited. To fill this gap, we conducted a genome wide-association study (GWAS) for POAG in individuals of African ancestry from the GIGA study and the BioMe biobank.

Methods : 1113 POAG cases and 1826 controls collected from Tanzania, South Africa and African Americans from the USA were genotyped on either the Illumina HumanOmniExpressExome or HumanOmni2.5Exome Beadchip. Genotypes were imputed to 1000 Genomes reference panel. The association between genotypes and susceptibility to POAG was tested using logistic regression assuming an additive genetic model, adjusting for age, sex and ethnic substructure. Top SNPs (P < 1 x 10^-6) from the discovery stage were followed up in a replication comprising four independent studies from South African, Ghanian, Nigerian and African American descent (Eyes of Africa Genetic Consortium and the South London POAG case –control cohort comprising individuals of West African origin.

Results : First, we tested the association with 15 previously reported POAG SNPs. Using a local replication approach, we queried all SNPs within strong linkage disequilibrium (R²>0.8, European LD), and observed nominal significance (P<0.05) for three SNPs located in the TXNRD2, CDKN2B-AS1, and TMCO1 region. rs16984299 in TXNRD2, remained significant after correction for multiple testing (P_Bonferonni=0.049). A genetic risk score combining the known POAG loci was significantly associated with POAG in the GIGA study (OR, 1.56; 95%CI, 1.26-1.93;P=4.79 x 10^-5). Second, by genome-wide association testing we identified one novel locus, rs141186647 in EXOC4 , reaching genome-wide significance in the discovery stage. Replication in four predominantly West African ancestral studies was unsuccessful mostly due to high degree of genetic heterogeneity observed at this locus.

Conclusions : We conducted the first GWAS of POAG in continental Africans. We verified the European glaucoma gene TXNRD2, and identified a novel locus encompassing EXOC4. A genetic risk score showed that the combined effect of the known loci from European/Asian GWAS was associated with POAG in Africans.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.