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.