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Kent Taylor, Xiuqing Guo, Linda M Zangwill, Jeffrey M Liebmann, Christopher A Girkin, Robert M Feldman, Harvey Dubiner, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Maggie CY Ng, Yii-Der Ida Chen, Radha Ayyagari, Jerome I Rotter, Robert N Weinreb; Genomic Architecture of POAG in Individuals of African Descent --African Descent & Glaucoma Evaluation Study (ADAGESIII)--. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5137.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the genomic architecture of primary open angle glaucoma (POAG) in individuals of African Descent (AD).
1875 POAG cases and 1709 controls, all self-identified as having African descent (AD) from ADAGESIII and Wake Forest University were genotyped with the Illumina MegaChip. Genotype data were imputed to the 1000 Genomes dataset. The association of SNPs with POAG and advanced POAG was tested using a linear mixed model that corrects for sample relatedness and population stratification. Genetic risk scores were calculated using two methods and tested by plotting the Area Under the Receiver Operator Characteristics Curve (AUC).
After quality measures, genotype data for 870,067 autosomal SNPs with a minor allele frequency >0.005 for cases and controls were generated. After imputation to the 1000 Genomes dataset, 17,794,691 SNPs met quality of imputation r2>0.7 and control minor allele frequency > 0.005. Association of a novel locus, ENO4, was observed at SNP rs85815146 (advanced POAG, effect 0.36, p<3x10-8). In addition to association with the 9p21 signal previously observed in individuals of European descent (ED) (rs2383204; p<2x10-5), an independent, novel, AD 9p21 signal was observed (rs79721419; p<6x10-5). AD specific signals were also observed in the FNDC3B (rs111698934, p<6x10-6) and the GAS7 (rs8080535, p<1x10-4) loci. An AUC of 0.62 was observed with a score composed of the 11 SNPs in the previously reported ED POAG loci. By using a penalized matrix decomposition, risk scores with AUC = 0.74 and AUC = 0.94 were obtained by adding 50 and 400 AD SNPs respectively.
These observations support the concept that GWAS in African-Americans will contribute to the study of the genomics of POAG in all populations by providing novel loci (ENO4), by providing novel signals in prior loci (9p21), and by advancing the fine-mapping of regions due to shorter linkage disequilibrium (FNDC3B, GAS7). The observed increase in AUC observed by adding AD SNPs supports the concepts that a great deal of AD specific genomic information remains in these data and that further collaborations are warranted for its identification.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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