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G. M. Acland, J. G. Mezey, A. R. Boyko, C. Gao, W. Wang, C. D. Bustamante, G. D. Aguirre, O. Goldstein; Whole-Genome Association Study Identifies the Canine Cone-Rod Dystrophy 2 Locus. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4046.
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Canine Cone-Rod dystrophy 2 (crd2) is an early onset, hereditary retinal degeneration identified in the American Pit Bull Terrier dog breed. It is characterized by initial severe day-blindness, progressing to total blindness by 1 year. A colony segregating the disease has been established.
To identify the locus responsible for Cone-Rod Dystrophy 2 by whole-genome association study (WGAS).
DNA was extracted from 14 crd2-affected cases and 13 unaffected related controls using standard protocols. A WGAS was undertaken using the Affymetrix Version 2, Canine SNP chip following the standard protocol. Genotypes were called using "MAGIC" algorithm and tested for association using Fisher’s Exact test. A Bonferroni correction for multiple tests set the significance threshold at -Log10(p) > 6.39.
Two potentially associated loci were identified, although neither passed the significance threshold. The lower of the 2 peaks yielded a signal of 4.17. Linkage analysis to crd2 in pedigrees showed no co-segregation, suggesting a false positive hit. The second locus on CFA33 included 5 SNPs with a signal of 6.13, approaching the Bonferroni threshold. Linkage analysis showed significant co-segregation. Haplotype analysis identified a 2.7 Mb homozygosity block- the presumed crd2 Linkage Disequilibrium interval. Candidate genes evaluation is now in progress.
Carefully selected case and control groups for a WGAS, with as few as 13-14 dogs per group, successfully identified a region on CFA33 that potentially harbors the crd2 gene. Combined WGAS and Linkage analysis can exclude false positives and confirm true positive association hits even if genome wide significance thresholds are not achieved.
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