Cross-species analysis of genetic architecture and polygenic risk scores for non-contact ACL rupture in dogs and humans

Non-contact anterior cruciate ligament (ACL) rupture is a common heritable orthopaedic disease with serious long-term sequelae in humans and dogs, with many patients affected with moderate to severe osteoarthritis after diagnosis. The use of dog genetic data is a powerful approach to enrich human genome-wide association studies. Current clinical dogma views ACL rupture as an injury-driven event. Familial risk has been recognized in both species for many years. However, it is unclear how genetic effects interact with environmental risk to influence non-contact ACL rupture risk. We comprehensively investigated non-contact ACL rupture heritability, genetic architecture, genetic selective pressure, sharing of risk genes and biological pathways between two species, and polygenic risk score (PRS) prediction of disease risk. We confirmed moderate non-contact ACL rupture heritability in both species. In the dog model, hotspots of regional heritability were identified. We showed that non-contact ACL rupture is a disease under negative selection with a highly polygenic architecture in both species, with thousands of variant effects acting together to influence disease risk. Notably, we also confirmed the sharing of risk genes in the two species. Our findings challenge the dogma that non-contact ACL rupture is predominantly due to a single maneuver that catastrophically overloads the ACL. Despite the potential relevance of PRS prediction to orthopaedic disease, studies investigating its applicability are scarce. Our findings suggest that accurate PRS prediction of non-contact ACL rupture risk is an achievable research goal in both species. Clinical implementation would identify individuals for personalized medical and physical therapy care and lifestyle modification.