Modified Abstract: The current COVID-19 pandemic causes illness, hospitalizations and deaths worldwide, and profoundly impacts global health including economic health. The severity of disease varies widely, but there is no evidence that a specific virus sequence is responsible. An estimated 15-20% of all infections require hospitalization with many of these patients progressing to acute respiratory distress (ARDS) and mechanical ventilation, cardiac and renal failure. Known co-morbidities such as older age (>65 years), diabetes, hypertension, pre-existing pulmonary disease, obesity, and smoking pre-dispose to such severe outcomes. However, among hospitalized cases there is tremendous heterogeneity in age, sex, and comorbidities with no clear understanding of disease pathogenesis. Viral differences and inoculum dose to not appear to be driving the differences in disease severity suggesting that host factors are important. Host genetics may influence pathogenesis in multiple ways including differences in immune response and viral shedding and partially explain this disease heterogeneity. A clear host genetic difference is especially likely to explain the instances of severe disease among young persons with no known comorbidities. Our hypothesis is that one or more host genetic polymorphisms predisposed otherwise healthy individual to severe COVID-19 infection. We plan to enroll 1500 individuals across the disease spectrum and to evaluate their serology for exposure and clinical characteristics and interrogate the human genome. We will also evaluate the hospitalized patients for cytokine expression and association with the host genome. This proposal has the potential provide an understanding of COVID-19 disease pathogenesis and identify those at greatest risk.