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Genome Wide Association Studies in Glaucoma

Ananth Viswanathan

Paul Foster, Peter McGuffin, Paul Mitchell, Fotis Topouzis.

According to the World Health Organisation, glaucoma is the commonest cause of irreversible blindness. Although the disease cannot be reversed, timely intervention retards disease progression and lessens the impact on quality of life. It is well known that the features of the eye which contribute to the clinical appearance of glaucoma are strongly genetically determined: published heritability estimates for intraocular pressure, optic nerve cup/disc ratio and retinal nerve fibre layer thickness range from 29% to 95%. At present, detection and risk stratification in glaucoma are crude. Half of glaucoma cases in the populations of developed countries remain undiagnosed. The pathogenesis of the disease is unknown and accurate predictions of which patients will suffer from rapidly progressive disease cannot be made.

The three known genes (MYOC, OPTN, WDR36) implicated in primary open angle glaucoma (POAG) by classical linkage studies probably contribute to the pathogenesis of POAG in less than 5% of cases in the general population. Genes accounting for a more significant proportion of the known heritable component of POAG remain to be identified.

The quantitative trait loci (QTLs) found as a result of this research will initially enable better risk stratification in glaucoma and the more appropriate distribution of clinical resources. Knowledge of the QTLs involved is likely to lead to gene discovery which will elucidate the pathogenesis of POAG and provide therapeutic targets.

Genome-wide association studies are planned to find the QTLs associated with the two quantitative traits of primary interest in glaucoma, both highly heritable, appropriately adjusted for covariates. The first is intraocular pressure, a major risk factor for glaucoma and currently the only modifiable one. The second is optic nerve cup/disc ratio, a measure of the morphology of the optic nerve which increases as glaucoma progresses. The initial study will be on a cohort of approximately 3000 individuals which has been accurately phenotyped and for which DNA is available. The replication study will be on a combination of two other similar cohorts. The first consists of over 600 individuals for whom DNA and phenotypic data are available. (This is part of a larger cohort of approx. 2500: all have been phenotyped and DNA may become available for the remaining 1800 in the future). The second consists of approximately 3900 individuals all of whom have already undergone genome-wide high density SNP analysis at the Sanger Institute. This cohort is in the process of being phenotyped. Key goals are the identification of QTLs associated with intraocular pressure and optic nerve cup disc ratio.