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J. R. Samples, J. Charlesworth, P. Kramer, A. Hewitt, J. E. Craig, T. Dyer, D. Mackey, J. Blangero; The Path to Open Angle Glaucoma Gene Discovery: Using the Endophenotypes, Intraocular Pressure, Central Corneal Thickness and Cup-To-Disc Ratio to Identify POAG-Related Loci. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2176.
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The purpose of this study was to identify genetic contributions to primary open-angle glaucoma (POAG) through investigations of three quantitative components of the POAG phenotype, intraocular pressure (IOP), vertical cup-to-disc ratio (VCDR) and central corneal thickness (CCT).
Genome-wide multipoint variance components linkage analysis of maximum recorded IOP, CDR and CCT were conducted using data from a large multi-center study of extended, Caucasian POAG families from Australia and North America, including 1181 people from 22 extended pedigrees. Variance components analysis was conducted using SOLAR. A population ascertainment correction was used to correct for sampling bias and an empirical LOD adjustment applied to correct for any non-normal trait distributions. This study was conducted in accordance with tenets of the Declaration of Helsinki. Informed consent was obtained from all participants.
All three traits showed evidence of significant heritability. Multipoint linkage analysis of maximum recorded IOP produced a peak LOD score of 3.87 near marker D3S3672. Analysis of maximum recorded VCDR gave a peak LOD score of 4.02 between D3S1558 and D3S1569, which is coincident with the GLC1C locus on chromosome 3q. Multipoint analysis of minimum recorded CCT produced a peak LOD score of 3.97 near marker D15S118. Age, sex and their interactions as well as population of origin were included as covariates in all analyses.
Identification of glaucoma susceptibility genes has been hampered by the complexity of the disease, as well as the late age of onset. Using a different approach than the classical Mendelian analysis, we successfully mapped loci for three POAG endophenotypes with LOD scores ≥ 3.0, Thus, utilization of quantitative traits for identification of POAG susceptibility genes combined with the power of family based linkage analysis appears to be a viable option that has the potential for breaking through the barriers to finding new POAG genes.
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