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Argus J Athanas-Crannell, Mark Christopher, Yongwook Choi, Agnes Chan, Linda M Zangwill, Jerome I Rotter, Jeffrey M Liebmann, Christopher A Girkin, Robert M Feldman, Harvey Dubiner, Yii-Der Ida Chen, Kent Taylor, Xiuqing Guo, Radha Ayyagari, Robert N Weinreb, Nicholas Schork; Gene-Based Analysis Leveraging Whole Genome Sequencing (WGS) Data on Individuals with Multiple Longitudinal Glaucoma Related Phenotypes Shows Evidence for Genetic Factors in Open Angle Glaucoma Progression. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1182.
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To evaluate the relationship between genetic variants obtained from WGS and multiple glaucomatous visual field progression phenotypes.
WGS data was collected at an average read depth of 30x using the Illumina X10 technology on 600 glaucoma patients or glaucoma suspects of Northern European descent, and 71 normal controls. We focused our analyses on a subset of 440 glaucoma patients who had longitudinal visual field (VF) test results available (4.5 –12 years) allowing us to assess genetic factors contributing to glaucoma progression with VF summary measures and Garway-Heath visual field (GHVF) sector based loss of VF mean sensitivity or increase in the number of test locations outside normal limits (p<0.05) for pattern deviation. 6.2 Million SNPs were selected for analysis based on filters for Minor Allele Frequency (MAF > 5%), Hardy-Weinberg Equilibrium (HWE), and total called genotypes across all loci interrogated (> 90%). Using regression analysis techniques, we tested SNP associations against disease progression of GHVF sectors. Results from each GWAS on GHVF phenotypes were aggregated within genes and genic/intergenic regions, and SNPs that were above a genome-wide suggestive threshold (p < 1e-5) and with sufficient Linkage Disequilibrium LD support were selected for further analysis. A gene-based analysis was performed by looking at enrichment of significant SNPs across multiple phenotypes.
Three genes previously shown to be associated with glaucoma, TMTC2 (p =1.622e-06), NR2F2 (p =3.365e-06), and ABCA1 (p =1.705e-04), exhibited evidence for association with multiple glaucoma progression glaucoma measures. Other intergenic regions, with no previous association to the disease were identified as novel influential loci. The strongest candidate, is between CCDC85A-VRK2 (p =8.984e-07). CCDC85A is paralog to CCDC85C which plays a role in radial glia maintenance.
Our data confirms known glaucoma genes that harbor variants are associated with disease progression in addition to a wide variety of Glaucoma-related phenotypes in European population.
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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