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Clinical Trial
. 2018 Oct;137(10):847-862.
doi: 10.1007/s00439-018-1943-7. Epub 2018 Oct 13.

Genome-wide Association Study of Primary Open-Angle Glaucoma in Continental and Admixed African Populations

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Free PMC article
Clinical Trial

Genome-wide Association Study of Primary Open-Angle Glaucoma in Continental and Admixed African Populations

Pieter W M Bonnemaijer et al. Hum Genet. .
Free PMC article

Abstract

Primary open angle glaucoma (POAG) is a complex disease with a major genetic contribution. Its prevalence varies greatly among ethnic groups, and is up to five times more frequent in black African populations compared to Europeans. So far, worldwide efforts to elucidate the genetic complexity of POAG in African populations has been limited. We conducted a genome-wide association study in 1113 POAG cases and 1826 controls from Tanzanian, South African and African American study samples. Apart from confirming evidence of association at TXNRD2 (rs16984299; OR[T] 1.20; P = 0.003), we found that a genetic risk score combining the effects of the 15 previously reported POAG loci was significantly associated with POAG in our samples (OR 1.56; 95% CI 1.26-1.93; P = 4.79 × 10-5). By genome-wide association testing we identified a novel candidate locus, rs141186647, harboring EXOC4 (OR[A] 0.48; P = 3.75 × 10-8), a gene transcribing a component of the exocyst complex involved in vesicle transport. The low frequency and high degree of genetic heterogeneity at this region hampered validation of this finding in predominantly West-African replication sets. Our results suggest that established genetic risk factors play a role in African POAG, however, they do not explain the higher disease load. The high heterogeneity within Africans remains a challenge to identify the genetic commonalities for POAG in this ethnicity, and demands studies of extremely large size.

Conflict of interest statement

Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.

Figures

Fig. 1
Fig. 1
Genetic Risk Score. Genetic risk score based on the 15 known POAG-loci identified in Europeans and Asians GWAS (rs1192415, rs28504591, rs4619890, rs2745572, rs11969985, rs4236601, rs284489, rs10712703, rs2472493, rs58073046, rs7137828, rs10483727, rs3785176, rs9897123, rs16984299). Participants were grouped into quintiles of the genetic risk scores. Green circles represent the POAG odds ratio (adjusted for age, sex and principal components) when comparing each quintile to the lowest quintile (Q1 = reference line). The green-capped lines represent 95% CI of the POAG odds ratios. Bars represent the percentage of POAG cases (dark blue) and controls (light blue) per quintile.
Fig. 2
Fig. 2
Study design
Fig. 3
Fig. 3
Manhattan plot for the association of genome-wide SNPs with primary open-angle glaucoma in GIGA BioMe meta-analysis. Manhattan plot of the GWAS meta-analysis of GIGA and BioMe (N=1113cases/N = 1826 controls). The figure shows −log10-transformed P values for all SNPs. The upper dotted horizontal line represents the genome-wide significance threshold of P < 5.0 × 10−8; the lower dotted line indicates a P value of 1 × 10−6. Green dots represents variants in that are in linkage disequilibrium (r2 > 0.6 1000 Genomes African ancestry) with the top SNP rs141186647.
Fig. 4
Fig. 4
Regional Plots for SNPs P < 1 × 10−6 in the discovery stage (stage 1)

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