Mutation Detection for Legg Calve Perthes Disease in Small Breed Dogs
Principal Investigator: Rory Todhunter
Co-PI: Jessica Hayward
DESCRIPTION (provided by applicant):
Legg Calve Perthes Disease (LCPD) is a complex trait characterized by slow destruction of the femoral head of small and toy breed dogs accompanied by clinical signs of hip pain and lameness. Compared to mixedbreed dogs, the odds ratios for developing this trait range from ~4 to ~191 in small breed dogs. A genome-wide association study (GWAS) was conducted using 85 cases of LCPD and 102 controls, consisting of small dog breeds (such as the Cairn Terrier and Yorkshire Terrier), as well as 8 small mixed-breed dogs. The most significant association is at canine chromosome (CFA) 6: 30,534,617bp with a P-value of 7.6x10-7 (not reaching the Bonferroni-adjusted threshold for genome-wide significance but over the permutation threshold). This locus increases the genetic risk of LCPD in West Highland White Terriers and Miniature Poodles with an odds ratio of ~3. Genotype imputation confirmed the CFA6 locus, but the P-value was below the accepted imputation significance threshold of 1x10-8. Based on this preliminary data, we hypothesize that a locus on CFA6 contains one or more variants that are major contributors to the risk of developing LCPD. To support our preliminary results, we propose three specific aims: (1) to genotype a further 86 cases of LCPD and 86 breedmatched controls (DNA already available) to confirm the CFA6 association in an independent cohort. (2) To perform haplotype analysis of all 247 genotyped dogs (preliminary data and Aim 1) to discover the narrowest linkage disequilibrium (LD) interval shared across breeds. (3) To perform whole-genome sequencing of 10 affected LCPD dogs and 10 unaffected LCPD dogs, from five different breeds, for variant discovery within the interval(s) of interest as identified in Aims 1 and 2. We will screen the variants for their mutation prediction. This research will facilitate functional testing of putative mutations and subsequent development of a genetic screening test to identify carriers of LCPD variants in susceptible breeds to inform breeding decisions. Based on a molecular understanding of this disease, novel avenues for early intervention in dogs and possibly adolescent children, who suffer from a very similar debilitating disease, can be explored.