OBJECTIVE: Cruciate ligament rupture (CR) in Labrador Retrievers is a complex polygenic disease with high heritability. The environmental contribution to CR risk remains poorly characterized. An accurate genetic risk test for CR in the Labrador Retriever has been developed. This enables evaluation of environmental risk with knowledge of genetic disease predisposition through study of dogs with phenotypic disease status that is discordant with their genetic risk. The objective of this study was to identify environmental factors that contribute to CR in Labrador Retrievers through evaluation of dogs with clinical phenotypes that are discordantly predicted with the use of genetic markers. METHODS: Dogs were prospectively recruited between January 2013 and December 2022. To study discordant subjects, case dogs with a posterior risk probability value <
0.75 and control dogs with a posterior risk probability of >
0.25, determined with the use of an average of 8 statistical models, were selected. The environmental factors investigated were neuter status, age of neuter, withers height measured at the dorsal-most ridge between the scapulae, weight, body mass index, and athletic activity. RESULTS: Ninety three dogs were discordant: 58 dogs were discordant CR cases, and 35 dogs were discordant CR controls. Neutering before 12 months of age was a significant risk factor for CR development. Sex, neuter status, or status as an athlete was not associated with CR risk. CONCLUSIONS: Neutering before 12 months of age influences risk of CR in Labrador Retrievers. CLINICAL RELEVANCE: This information can inform management decisions about Labrador Retrievers regarding age of neutering, body condition, and athletic activity. The primary factor influencing CR development in Labrador Retrievers is polygenic intrinsic genetic risk.