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Jamie E. Craig, Alex W. Hewitt, Shiwani Sharma, Stuart Macgregor, Paul Mitchell, Glyn Chidlow, John Wood, Robert Casson, David A. Mackey, Kathryn P. Burdon; Genome Wide Association Study For Open Angle Glaucoma Blindness Identifies Novel Replicated Susceptibility Loci. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5317.
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© ARVO (1962-2015); The Authors (2016-present)
To identify genetic loci associated with severe vision loss from open angle glaucoma (OAG), using cases from the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG).
A Genome wide association study was performed using a discovery cohort of 650 cases of advanced OAG genotyped using Illumina Omni1 arrays and compared with 3956 controls genotyped with Illumina HumanHap610 or HumanHap660 arrays. Replication cohorts were 334 further cases of advanced OAG from the ANZRAG, and 578 less severe Australian OAG cases with elderly ethnically matched controls who were examined to exclude OAG (n=432 and n=504 respectively).
After data cleaning, the discovery analysis was performed on 590 advanced glaucoma cases and revealed regions on chromosome 1q24 and 9p21 which reached genome wide significance (OR 1.68, p = 6.1 x 10-10, and OR 1.50, p = 4.7 x 10-9 respectively). In each region multiple SNPs were associated. Replication analysis using two replication cohorts showed significant association at both regions in both replication cohorts (combined replication OR 1.41, p = 5.4x10-4, and OR 1.27, p = 7.94x10-4). The strength of association was greater in the advanced OAG replication set. Ocular expression patterns for genes at both loci were determined by RT-PCR and immunohistochemistry revealing strong expression in retinal ganglion cells, and weaker expression in trabecular meshwork and ciliary body.
The severe disease registry approach, combined with genome wide association methodology has defined 2 genetic regions with strong and replicated association to OAG. Genes in these regions may be implicated in retinal ganglion cell apoptosis susceptibility. Defining the genetic variants responsible for these associations may be useful for predicting progression to glaucoma blindness.
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