BackgroundPatients with osteoarthritis (OA) are exposed to an increased risk of adverse outcomes of COVID-19, and they tend to experience disruption in access to healthcare services and exercise facilities. However, a deep understanding of this comorbidity phenomenon and the underlying genetic architecture of the two diseases is still unclear. In this study, we aimed to untangle the relationship between OA and COVID-19 outcomes by conducting a large-scale genome-wide cross-trait analysis.MethodsGenetic correlation and causal relationships between OA and COVID-19 outcomes (critical COVID-19, COVID-19 hospitalization, and COVID-19 infection) were estimated by linkage disequilibrium score regression and Mendelian Randomization approaches. We further applied Multi-Trait Analysis of GWAS and colocalization analysis to identify putative functional genes associated with both OA and COVID-19 outcomes.ResultsSignificant positive genetic correlations between OA susceptibility and both critical COVID-19 (rg=0.266,P=0.0097) and COVID-19 hospitalization (rg=0.361,P=0.0006) were detected. However, there was no evidence to support causal genetic relationships between OA and critical COVID-19 (OR=1.17[1.00-1.36],P=0.049) or OA and COVID-19 hospitalization OR=1.08[0.97-1.20],P=0.143). These results were robustly consistent after the removal of obesity-related single nucleotide polymorphisms (SNPs). Moreover, we identified a strong association signal located near theFYCO1gene (lead SNPs: rs71325101 for critical COVID-19,Pmeta=1.02×10-34; rs13079478 for COVID-19 hospitalization,Pmeta=1.09×10-25).ConclusionOur findings further confirmed the comorbidity of OA and COVID-19 severity, but indicate a non-causal impact of OA on COVID-19 outcomes. The study offers an instructive perspective that OA patients did not generate negative COVID-19 outcomes during the pandemic in a causal way. Further clinical guidance can be formulated to enhance the quality of self-management in vulnerable OA patients.