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B. Zangerl, S. J. Lindauer, A. Gupta, S. E. Pearce-Kelling, G. M. Acland, G. D. Aguirre; WGA Studies to Identify Potential prcd Disease Modifier Candidate Regions. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4095.
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© ARVO (1962-2015); The Authors (2016-present)
Progressive rod-cone degeneration (prcd), a retinal blinding disorder shared among at least 27 different dog breeds, is caused by a single base pair substitution in the PRCD gene located in the centromeric region of CFA9. Breed specific variation in time of onset and progression of the disease was previously shown to stably segregate with the original phenotypic trait, thus, a modifier locus was thought to exist in genomic proximity to the prcd locus on CFA9. Whole genome wide association (WGA) studies were applied to compare animals affected by either the fast or slow forms of prcd, against prcd-carrier and normal animals in order to identify potential disease modifier loci.
An initial set of 11 and 13 animals, affected by the fast or slow phenotype respectively, was compared to a control group comprised of 10 known carriers using the canine Affymetrix 127,132 SNP v2 full set chip. The analysis was then extended to a total of 44 prcd-affected animals compared to 82 animals with homozygous normal genotypes. Quantitative trait analysis with Bonferroni corrected p-values was performed using PLINK to identify significant markers.
Initial focus on CFA9 identified ACCN1 and RGS9 as potential prcd modifiers. Both genes underwent exons screens identifying additional polymorphisms and repetitive elements. At least 7 different haplotypes were observed for ACCN1 to have no association with either the disease phenotype or breed. Similar analysis is currently underway for RGS9. The extended analysis has refocused our investigation on a third area between these two genes which and is currently under investigation for potential disease modifiers.
Two potential modifiers of prcd located on CFA9, ACCN1 and RGS9, are likely excluded from association with disease phenotype, and the screen has been extended to additional genomic areas of interest. Preliminary data suggest that the modification of the disease is either caused by multiple factors and/or a simple mode of inheritance is not sufficient to explain observed variation in phenotype. We are presently examining more extensive analytical modeling methods of our data set to further refine regions that have a modifying effect on retinal disease phenotype.
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