SUMMARY Located within the human Major Histocompatibility Complex (MHC) chromosome 6p21, the Human Leukocyte Antigen (HLA) region is the most medically important region of the human genome. Variation in the HLA region has been associated with over 150 diseases and conditions, including infectious disease, cancers, and major drug-hypersensitivities. While little is known at this point about the impact of host genetic factors in COVID-19, the epidemiology to-date reveals wide variation in disease course among confirmed cases of infection that does not appear to be fully explained by known risk factors. Because of its pivotal role in the immune response understanding the role of HLA variation promises to provide important insights relevant to understanding the immunopathogenesis of COVID-19, while informing vaccine development and potential immunotherapies. In Specific Aim 1, we will exploit an existing data resource, partnering with the National Marrow Donor Program and DKMS registries to collect data on COVID-19 symptoms, testing and outcomes using a novel, validated smartphone app in a very large sample (N=300,000-500,000) of volunteer bone marrow donors with pre-existing HLA genotyping data, allowing an extraordinarily well-powered examination of the role of these genes in disease. In Specific Aim 2, we will employ a novel, validated method for next-generation sequencing of the extended MHC (~5Mb), including all classical and non-classical HLA loci, as well as over 150 additional immune system loci, in large and diverse cohorts of COVID-19 patients (N=2000), as well patient cohorts with longitudinal clinical data and extensive immunoprofiling (N=300). Finally, in Specific Aim 3 we will contextualize these association studies through examination of the role of HLA presentation of SARS-CoV-2 antigens. In summary, we will leverage large and diverse patient cohorts alongside cutting edge technology and molecular biology to reveal the role of these important immune loci in COVID-19.