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M.A. Hauser, F.L. Graham, R.R. Allingham, K. LaRocque–Abramson, C.M. Santiago, E. DelBono, L. Olson, J.L. Haines, J.L. Wiggs, M.A. Pericak–Vance; Evidence for linkage but not association to the GABRB3 region of chromosome 15 in a subset of primary open angle glaucoma (POAG) families. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4394.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Previously, we employed Ordered Subset Analysis (OSA) to identify a homogenous subset of POAG families linked to chromosome 15q in order to refine our candidate region for analysis (Allingham, et al, ASHG 2002). We used age at diagnosis as a surrogate for age of onset as a covariate in the analysis. The peak OSA lod score reached a maximal value of 3.05 in a subset of 15 families with a family specific mean age at diagnosis < 49 years of age at the GABRB3 locus (12.4 cM) (p = 0.011 by permutation test). Within this region are located three GABA receptor genes, GABRA5, GABRB3 and GABRG3. These genes are all expressed in the retina making them good candidate susceptibility genes. We have now conducted association analysis using a number of single nucleotide polymorphisms in order to obtain further evidence for or against the involvement of these genes in POAG. Methods: Using the 15 families (92 individuals) that were identified by OSA as being a homogeneous subset of the POAG data set, we analyzed 21 single nucleotide polymorphisms (SNPs) within the GABRB3 gene and in the region located beyond the 3’ end of the gene. Both association and linkage were evaluated. In addition, the full coding region of all three GABR genes were sequenced. Results: Seven of the twenty–one SNPs showed positive linkage with a peak LOD score of 1.63 for SNP SNPEX1A–2. Allelic association analysis was not significant for any of the SNPs using the Pedigree Disequilibrium Test (PDT) (p≥0.05). Sequence analysis showecd no coding changes in any of the GABR genes. Conclusions: There is significant evidence for linkage using these SNPs, supporting the hypothesis that this region harbors a susceptibility gene for POAG. The lack of sequence changes in the GABR genes indicates either that 1) another gene is responsible for linkage to this region, or 2) mutations or polymorphisms involving gene regulatory regions have not yet been detected. The lack of allelic association indicates that there are most likely multiple family–specific sequence variants giving rise to POAG in these families, rather than a single common variant. This work was made possible by funding from Prevent Blindness and the Barkhouser Glaucoma Research Fund.
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