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Pirro G. Hysi, Jelle Vehof, Francis Carbonaro, Terri L. Young, David A. Mackey, Christopher J. Hammond; Identification of Candidate Genetic Loci Altering Susceptibility to Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5318.
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Early diagnosis of those at risk for glaucoma is a major potential benefit from predictive DNA testing and genetic research can be powerful tool for the improvement of our understanding of this disease. Genome-wide association studies (GWAS) have identified genetic associations with glaucoma endophenotypes such as optic disc size and cup:disc ratio, intraocular pressure, and central corneal thickness, and candidate genes have emerged using GWAS for glaucoma cases and controls. We performed a GWAS on glaucoma-susceptibility risk in an unselected population.
We have measured a variety of quantitative glaucoma-related endophenotypes including intraocular pressure, cup:disc ratio, optic disc area, central corneal thickness in a panel of 3,300 volunteer participants in the TwinsUK cohort drawn from the British general population, mean age 55 years (SD 13.4). We combined these phenotypes to generate one single quantitative phenotype obtained through a Factor Analysis, and based on the OHTS validated glaucoma prediction model (Arch Ophthalmol. 2002; 120: 714-720). This phenotype is meant to approximate the risk to glaucoma among the general population. A Genome-Wide Association analysis was performed using the Illumina HumanHap 300k Duo and the HumanHap610-Quad arrays, and imputation calculated with reference to the 1,000 Genomes Project. Analysis was performed using Merlin.
Our GWAS confirmed many loci known for their involvement in glaucoma or glaucoma-underlying quantitative traits (ATOH7, FOXO1, ZNF469). Novel loci were identified, and may act as a functional link between genes influencing several glaucoma sub-phenotypes and are evocative of the complexity of the disease etiology. Replication obtained in other populations, suggests that this association has a biological basis and as such these genes and their pathways are important targets for glaucoma treatment in the future.
We identified novel loci associated with a trait related to the risk of developing glaucoma among the general population. Despite modest values in predicting risk in individuals, these loci are valuable in improving our knowledge on the disease and enriching the list of potential targets for the treatment of the disease.
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