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Jamie Craig, Alex Hewitt, Stuart Graham, Paul Healey, Robert Casson, Paul Mitchell, John Landers, Stuart MacGregor, David Mackey, Kathryn Burdon; Identification of further novel genome wide significant loci for open angle glaucoma blindness utilizing the Australian and New Zealand Registry of Advanced Glaucoma. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4503. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
The pathogenesis of glaucoma, the leading cause of irreversible blindness remains poorly understood. There is a strong genetic basis for open angle glaucoma (OAG), and replicated susceptibility genes have been identified through genome wide association studies (GWAS). Using severely affected cases enhances genetic power to detect associations, and in a previous GWAS of individuals with advanced visual field loss from OAG we found strong associations at chromosome 1q24 (TMCO1) and 9p21 (CDKN2B-AS1). Using further cases recruited through the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG) we aimed to perform an extended study doubling the size, with the aim of identifying further common susceptibility loci for glaucoma blindness.
1184 cases recruited through ANZRAG met entry criteria, which are advanced field loss due to OAG with either visual acuity worse than 20/200, severe global field loss, or field loss involving central fixation in the worst eye. These samples were genotyped on Illumina OmniExpress arrays and compared to 2761 examined controls from the Blue Mountains Eye Study, and 4642 unexamined controls from the publicly available Wellcome Trust Case Control Consortium, and the Illumina iControl databases. Following data cleaning and removal of genetic outliers by principal components analysis, association analysis was conducted in PLINK.
Genome wide significant associations (p < 10-8) were identified at 9 loci. As expected, the previously identified regions (CDKN2B-AS1, 9p21, OR 1.46, p=2x10-15, and TMCO1, 1q24, OR 1.56, p=1.6x10-14) remained strongly associated. We also confirmed SIX1/SIX6 on chromosome 14q23 at genome wide significance (OR 1.29, p=5x10-9). Single nucleotide polymorphisms (SNPs) at a further 6 loci were associated at the level of genome wide significance (4p12, p=3.1x10-20; 1q32, p=5x10-15; 4p16, p=4x10-10; 7p21, p=1.3x10-8; 3p12, p=1.7x10-8; 7q31, p=2x10-8). Further analysis and replication studies are ongoing. Genes at several of these loci are strong functional candidates for OAG.
The use of extreme phenotypes is a successful and cost-effective strategy to identify genes contributing to OAG blindness. These discoveries are likely to be of importance in directing future glaucoma research in risk profiling, and developing novel therapeutic targets.
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