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

PLoS One. 2019 Oct 17;14(10):e0223094. doi: 10.1371/journal.pone.0223094. eCollection 2019.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anterior Cruciate Ligament / diagnostic imaging
  • Anterior Cruciate Ligament / physiopathology*
  • Body Size / genetics
  • Chromosome Mapping
  • Coenzyme A Ligases / genetics
  • Dog Diseases / diagnostic imaging
  • Dog Diseases / genetics*
  • Dog Diseases / physiopathology
  • Dogs
  • Femur / diagnostic imaging
  • Femur / physiopathology
  • Genome-Wide Association Study*
  • Genotype
  • Growth Hormone / genetics*
  • Insulin Receptor Substrate Proteins / genetics
  • Joint Diseases / genetics
  • Joint Diseases / physiopathology
  • Joint Diseases / veterinary
  • Myosin Heavy Chains / genetics
  • Osteoarthritis / genetics
  • Osteoarthritis / physiopathology
  • Osteoarthritis / veterinary
  • Repressor Proteins / genetics
  • Tibia / diagnostic imaging
  • Tibia / physiopathology

Substances

  • Insulin Receptor Substrate Proteins
  • Repressor Proteins
  • Growth Hormone
  • Myosin Heavy Chains
  • Coenzyme A Ligases
  • long-chain-fatty-acid-CoA ligase

Associated data

  • Dryad/10.5061/dryad.266k4