PROJECT SUMMARY In addition to causing millions of cases and hundreds of thousands of deaths, the Coronavirus disease 2019 (COVID-19) pandemic has brought life and economic activity to a near standstill in many parts of the world. A coordinated scientific effort is necessary to mitigate the widespread misery, morbidity and mortality inflicted by the pandemic. The goal of this supplemental application is to contribute to informatics and genomics efforts to identify the genomic basis of susceptibility to and complications of COVID-19. The wide spectrum of disease severity with COVID-19 is only partially explained by age and medical comorbidities and genetic factors are likely to play a key role. Identifying genomic factors impacting COVID-19 case status and complications is important for risk stratification, identifying new pathophysiologic pathways for drug development/repurposing, and improved understanding of the biology of SARS-CoV-2 infection and its complications. As part of the electronic Medical Records and Genomics (eMERGE) since its inception in 2007, Mayo investigators have considerable experience in using the electronic health record (EHR) for genomics research. We will develop electronic phenotyping algorithms to ascertain COVID-19 case status, complications and fatality, to identify genomic variants associated with adverse outcomes. Using DNA samples linked to the EHR, we will perform genomic analyses to identify common and rare variants associated with case status, case severity and case mortality. We will collaborate with health systems and consortia in the US and around the world to increase the power and rapidity of the genomic studies. Our specific aims are: Specific Aim 1: Develop and validate electronic phenotyping algorithms to ascertain COVID-19 related phenotypes including case control status, i.e., individuals tested and those were identified to be positive for COVID-19, and disease severity, in particular cardiovascular complications including myocardial injury/infarction, arrhythmias, coagulopathy as well as large vessel thrombosis. Specific Aim 2: Perform genomic association analyses to identify variants associated with susceptibility to infection with SARS-CoV-2 and its complications. We will compare test +ve vs test -ve individuals, mild vs hospitalized cases of COVID-19 and among the latter those who develop severe disease or die. In addition to genome-wide association studies (GWAS), we will conduct association studies of the HLA region and burden tests using sequence data.