The societal and patient-centered impacts of end-stage osteoarthritis (OA) among United States Veterans are profound. More than 30% of Veterans in the VA healthcare system have OA which is significantly higher than in the general population. VA treatment costs for OA are high, exceeding $880 million annually. Still, apart from pain and symptom management and end stage surgical intervention, there are no effective therapeutic treatments for OA. Despite prescribed rehabilitation post-surgery, Veterans who undergo total hip arthroplasty (THA) or total knee arthroplasty (TKA) experience profound deficits in health-related quality of life (HRQL), severe limitations in activities of daily living, increased healthcare utilization, and higher incidence of comorbidities. OA has a strong genetic component with heritability estimates >30%. Our research in the Million Veteran Program (MVP) cohort led to discoveries in key areas. First, our ancestry specific and multi-ancestry analyses in over 477,000 MVP and the UK Biobank (UKB) participants identified of novel genetic regions associated with OA. Second, OA frequency was higher in the MVP than in our replication cohort (UKB) despite using identical electronic health record diagnosis codes which may have hampered replication efforts. Third, our research in the MVP cohort demonstrated a higher OA heritability in African American and Hispanic Veterans than those of European White descent. Our overall goal is to identify pre- and post-rehabilitative biomarkers to enhance physicians’ intuition for predicting patient prognosis for Veterans with OA and/or PTOA. Toward this goal and to fill important knowledge gaps regarding the association of genetic factors with OA and outcomes, in Aim 1, a) we will confirm genetic variants associated with OA prevalence and progression to end- stage OA as well as b) develop and evaluate the performance of a polygenic risk score (PRS) to identify Veterans at risk of progression to total hip/knee joint arthroplasty; in Aim 2, we will identify genetic variants prognostic of THA/TKA recovery; and in Aim 3, we will determine whether genetic variants associated with the development of post-traumatic OA (PTOA) are distinct from known genetic determinants of idiopathic OA. We will identify biomarkers to enable targeted, precision pre-habilitation and post-surgical rehabilitation strategies improving mobility function, HRQL, and healthcare utilization among Veterans with OA.