Genetic mapping of distal femoral, stifle, and tibial radiographic morphology in dogs with cranial cruciate ligament disease.

Eleni Healey,Rachel J Murphy,Kei Hayashi,Marta Castelhano,Ursula Krotscheck,Jessica J Hayward,Rory J Todhunter,Adam R Boyko,Yuan-Ming Zhang

doi:10.1371/journal.pone.0223094

Abstract

Cranial cruciate ligament disease (CCLD) is a complex trait. Ten measurements were made on orthogonal distal pelvic limb radiographs of 161 pure and mixed breed dogs with, and 55 without, cranial cruciate partial or complete ligament rupture. Dogs with CCLD had significantly smaller infrapatellar fat pad width, higher average tibial plateau angle, and were heavier than control dogs. The first PC weightings captured the overall size of the dog’s stifle and PC2 weightings reflected an increasing tibial plateau angle coupled with a smaller fat pad width. Of these dogs, 175 were genotyped, and 144,509 polymorphisms were used in a genome-wide association study with both a mixed linear and a multi-locus model. For both models, significant (pgenome <3.46×10−7 for the mixed and< 6.9x10-8 for the multilocus model) associations were found for PC1, tibial diaphyseal length and width, fat pad base length, and femoral and tibial condyle width at LCORL, a known body size-regulating locus. Other body size loci with significant associations were growth hormone 1 (GH1), which was associated with the length of the fat pad base and the width of the tibial diaphysis, and a region on CFAX near IRS4 and ACSL4 in the multilocus model. The tibial plateau angle was associated significantly with a locus on CFA10 in the linear mixed model with nearest candidate genes BET1 and MYH9 and on CFA08 near candidate genes WDHD1 and GCH1. MYH9 has a major role in osteoclastogenesis. Our study indicated that tibial plateau slope is associated with CCLD and a compressed infrapatellar fat pad, a surrogate for stifle osteoarthritis. Because of the association between tibial plateau slope and CCLD, and pending independent validation, these candidate genes for tibial plateau slope may be tested in breeds susceptible to CCLD before they develop disease or are bred.

Highlights

While one study did not conclude tibial plateau angle (TPA) to be significantly different between dogs with cruciate ligament disease (CCLD) and dogs without CCLD, the findings suggested that increased TPA may be associated with increased severity of stifle radiographic osteoarthritis (OA) in dogs with CCLD.[11]
We measured a subset of stifle radiographs which were used to diagnose stifle OA resulting from CCLD in a previous genome wide association study (GWAS)[17, 20] and radiographs on additional dogs were added for the Principal component analysis (PCA)
Even though the difference was not large, the TPA was significantly higher in dogs with CCLD (116.6±3.9 ̊) than in control (114.5±4.8 ̊) dogs

Summary

Introduction

Body weight, age, and sex predispositions, there are differing conclusions regarding the role of the tibial plateau angle (TPA), or caudal tibial slope, in the pathogenesis of CCLD Measurement of this angle is necessary for surgeries performed to correct CCLD in dogs, such as a tibial plateau leveling osteotomy (TPLO), which decreases TPA, and tibial tuberosity advancement, which is designed to neutralize this slope. We have used PCA to analyze the genetic basis of other canine orthopedic traits including pelvic morphology.[19] The present study used PCs of 10 pelvic limb radiographic measurements, as well as the individual measurements (some of which are correlated to CCLD and secondary OA), in a linear mixed and a multi-locus model GWAS. Veterinarians, owners and dog breeders need better tools to inform preventative strategies and breeding decisions, and better therapy to prevent CCLD and the secondary OA that encumbers affected dogs

Materials and methods

Results

Discussion