Identification of a genetic marker for familial subvalvular aortic stenosis in dogs.

摘要

Subvalvular aortic stenosis is one of the most common congenital heart defects in dogs and has been demonstrated to be familial in some dog breeds and families of human beings. Although the pathology of this disease and outcomes have been well described in Newfoundland dogs, the literature is lacking a clear characterization of this disease on molecular, genetic and heritability levels. Several dog breeds are overrepresented in prevalence of SAS and it has been described to follow pedigree lines of golden retriever, Rottweiler, and Newfoundland dogs.;The principle hypothesis of this dissertation is that subvalvular aortic stenosis is familial in golden retriever, Rottweiler and Newfoundland dogs. A secondary hypothesis is that although the genetic architecture of these breeds is unique, genome-wide association studies (GWAS) can identify shared genetic loci associated with the development of SAS in these breeds.;Four manuscripts are presented within the dissertation. The first manuscript presents a phenotypic description and pattern of inheritance analysis in golden retrievers with SAS. Findings include the establishment of a disease scoring system based upon echocardiographic diagnosis parameters, confirmation of the familial nature of SAS in this breed and support for a pattern of inheritance that is either autosomal recessive or autosomal dominant with incomplete penetrance.;Manuscript two prepares for the genetic investigation of SAS in the three studied breeds, by first examining the genetic architecture of each breed through their extent of linkage disequilibrium (LD) in normal golden retriever, Rottweiler and Newfoundland dogs. All breeds are significantly different with marked chromosomal differences. Newfoundlands have the shortest extent of LD and Rottweilers the longest.;Manuscripts 3 and 4 present genome-wide association studies for each breed. Pertinent findings include the overlap of significance regions in Rottweiler and golden retriever dogs on chromosome 21, while Newfoundlands are most significantly associated with chromosome 20. These findings suggest that while some breeds of dog may share a causative mutation for SAS, it appears that SAS may be at least in part breed-specific. Future investigations include the analysis of candidate genes within the loci of interest identified by the GWAS techniques employed.