Influence of homozygosity on genomic structural variation analyses for predicting ACL rupture risk in the Labrador Retriever and Rottweiler

IntroductionAnterior cruciate ligament (ACL) rupture is a common orthopaedic disease in dogs, with varying prevalence and genetic susceptibility across different breeds. Here we investigate the association between genomic structural variation (SV) and ACL rupture risk in the Labrador Retriever and Rottweiler breeds.MethodsWe used 1,058 Labrador Retrievers (464 cases, 594 controls) and 108 Rottweilers (83 cases, 25 controls). Using breed‐specific de novo genome assemblies, we first characterized SV between Labrador Retriever and Rottweiler genomes to provide genomic context for breed-level differences. We then quantified runs of homozygosity (ROH) and evaluated the association between homozygosity measures (nROH, AVGROH, and FROH) and ACL rupture risk using breed‐specific and combined‐breed logistic regression models.ResultsThe association between homozygosity parameters and ACL rupture in the Labrador Retriever was not significant (P > 0.05 for all models). In contrast, inbreeding coefficient (FROH) was significantly associated with increased ACL rupture risk (OR = 2.011, 95% CI:1.120‐3.98, P‐value = 0.026) in the Rottweiler when sex and interaction effects were included in the model.ConclusionThese findings suggest a potential association between inbreeding and ACL rupture risk in Rottweilers. In addition, joint analysis of Labrador Retriever and Rottweiler data revealed multicollinearity between breed and homozygosity content, which highlights the heterogeneity of genetic risk factors across breeds. Our findings suggest that breed‐specific genetic models are crucial for understanding the genetic contribution to ACL rupture and for developing accurate genetic risk prediction tools. Given the relatively small and imbalanced Rottweiler dataset, independent validation in larger populations is warranted to further explore the potential breed‐specific genetic loci contributing to ACL rupture in the Rottweiler.