Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry

Abstract

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders.

Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma.

Design, settings, and participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma.

Exposures: Genetic variants associated with primary open-angle glaucoma.

Main outcomes and measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data.

Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry.

Conclusions and relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.

Figure 1.. Discovery Analysis of 2320 Individuals With Primary Open-Angle Glaucoma and 2121 Age-Matched Control Individuals

Single-nucleotide polymorphisms (SNPs) were only considered if they were assessed across all 4 genome-wide association discovery study sites. A total of 6 734 161 SNPs are included in this figure. The blue horizontal line indicates a threshold for suggestive statistical significance commonly used in genome-wide association studies (P = 10⁻⁵) and the red horizontal line indicates the threshold for genome-wide significance (P = 5 × 10⁻⁸). Multiple SNPs at the gene encoding for amyloid-β A4 precursor protein-binding family B member 2 (APBB2) have a significant association with primary open-angle glaucoma disease risk.

Figure 2.. Association at the Amyloid-β A4 Precursor Protein-Binding Family B Member 2 (APBB2) Locus on Chromosome 4

The association between single-nucleotide polymorphisms (SNPs) and primary open-angle glaucoma were plotted by genomic position on chromosome 4 and degree of statistical significance. The horizontal line shows the threshold for genome-wide significance, P = 5 × 10⁻⁸. The dots indicate the extent of linkage disequilibrium (LD) between each tested SNP with rs59892895 (based on pairwise r² values calculated from the discovery analysis). LD refers to the association between alleles of SNPs located close to one another on the same chromosome; SNPs in strong LD can serve as proxies for one another. Estimated recombination rates were plotted in light blue to reflect the LD structure in individuals with African ancestry. The estimated recombination rate shows the average frequency in which recombination occurs at a particular location. The extent of LD drops with increasing recombination rate. The horizontal lines accompanied by arrows in the lower panel of the plot reflect the genes mapping to the given genomic locations. The arrows indicate the direction of transcription of the genes. The horizontal lines labeled APBB2 and RBM47 reflect 2 different gene transcripts of different lengths for both genes.

Figure 3.. Association Between Amyloid-β A4 Precursor Protein-Binding Family B Member 2 (APBB2) rs59892895 and Primary Open-Angle Glaucoma Risk

The oblong data markers represent odds ratios, with the height of the data markers being inversely proportional to the standard error of the odds ratio. The diamonds represent the odds ratios after the meta-analysis, with the width representing the 95% CIs. Collections from the United States were taken from an African American population and the collection from South London was taken from a West African population. ADAGES indicates African Descent and Glaucoma Evaluation Study; AGGP, African Glaucoma Genetics Project; GWAS, genome-wide association study.