Prior research has shown that both environmental factors (e.g., healthcare access, socioeconomic status, and lifestyle) and human genetic variation influence susceptibility to infectious diseases. However, systematic analysis of how both sociodemographic and genetic factors contribute to differences in infectious disease susceptibility remains limited. Addressing this gap is important for improving clinical care and informing public health strategies. To this end, we will leverage genetic, electronic health record, and survey data from the All of Us biobank to test the hypothesis that human genetic factors contribute to differences in infectious disease susceptibility across genetic similarity groups independently of sociodemographic variables through the following aims: Aim 1: To identify demographic, socioeconomic, behavioral, and environmental factors associated with infectious disease susceptibility. In this aim, we will perform a comprehensive assessment of 227 demographic, socioeconomic, behavioral, and environmental variables, collected through All of Us surveys, on the prevalence of 336 infectious disease phenotypes across clusters of individuals who share a significant degree of genetic similarity. At the end of this aim, we will identify infectious diseases and associated contextual variables that are enriched or depleted in specific clusters. Aim 2: To identify human genetic factors associated with infectious disease susceptibility. In this aim, we will perform in-depth analyses of genetic variants that can be associated with infectious disease susceptibility. This aim will lead to the discovery of novel infectious disease susceptibility loci and risk variants. We will perform in silico functional analysis to gain insight to the function of these variants. In the short term, this study will result in identifying sociodemographic and genetic risk factors that underlie susceptibility to infectious diseases and clarify their relative contributions. Moreover, this project enhances our understanding of infectious disease biology and the genetic factors that affect interindividual variability in susceptibility to specific pathogens. In the long term, the results of this project can help the development of new public health policies or new diagnostic tests or drugs for infectious diseases.