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J.L. Wiggs, R.R. Allingham, J. Auguste, L. Olsen, K. LaRocque–Abramson, M.A. Hauser, E.A. DelBono, F.L. Graham, M.A. Pericak–Vance, J.L. Haines; Genomic Screen for adult–onset primary open angle glaucoma: Follow–up studies suggest loci on 14q11 and 15q. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4392.
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Purpose:We have previously completed a genome screen to identify the chromosomal locations of POAG susceptibility genes. Our initial studies provided evidence for POAG loci on chromosomes 2, 4, 14, 15, 17 and 19. The purpose of this study is to refine this analysis by adding: a third group of sibling pairs (195 sibling pairs total), unaffected pedigree members to help establish IBD, and additional markers in the regions of interest. Methods:86 families, representing a wide variety of ethnic backgrounds, were collected from the New England area and from the Southeast area of the United States. The families are mainly Caucasian (88%), and at least two members of each family are affected by POAG. POAG was defined as age of diagnosis greater than 35, intraocular pressure greater than 22 mm Hg in both eyes, glaucomatous optic nerve damage in both eyes, and visual field loss in at least one eye. Microsatellite repeat markers located in regions of interest were selected for analysis. Parametric analyses were performed with FASTLINK to calculate two–point LOD scores assuming both autosomal dominant and autosomal recessive models and allowing for genetic heterogeneity (Hetlods). Nonparametric analyses were performed with Allegro (Lod*). Results:With the current data set, both the parametric and nonparametric approaches provide evidence for POAG susceptibility loci on chromosome 14q11 (two–point lod score (autosomal dominant model 3.7, marker D14S264, LOD* 1.67) and 15q (two–point lod score autosomal dominant model 2.4, marker D15S165, LOD* 1.8). Haplotype analyses using markers located throughout the peak chromosome 14 and chromosome 15 regions show consistent segregation suggestive of dominant inheritance with reduced penetrance. Conclusions:In this study we have acquired substantial evidence for two novel loci for POAG on chromosomes 14 and 15. Our data suggest that these two loci likely represent a substantial portion of the genetic effect in POAG. A number of interesting candidate genes are located within each of the candidate regions on chromosomes 14 and 15 and sequencing of candidate genes with high priority based on appropriate ocular expression is currently underway.
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