PROJECT SUMMARY/ABSTRACT All of Us represents a unique resource to understand the genetic, environmental, and social determinants of complex traits across the broad diverse US population. All of Us encompasses underrepresented sexual and gender, racial and ethnic minorities, living in urban and rural areas. Currently whole-genome sequence data (WGS) is available on close to 100,000 subjects with 250,000 subjects expected by summer. Human disease is a complex interplay between both genes and environment. A better understanding of how disease is modified by genetic interactions with environmental, lifestyle and treatment factors as well as age, sex, and ancestry, will provide insights into prevention, early intervention, and potential therapeutic strategies to reduce the burden of disease and health disparities. Cardiometabolic traits such a BMI, glucose levels, lipid levels, blood pressure are important determinants cardiovascular disease. Understanding the genetic and environmental differences between ethnic groups is an essential component to understanding disease prevalence. We know traits can have different heritability across ethnic groups, shaped by thousands of years of independent evolution. This evolution is seen in the All of US WGS where ~12% of the markers are multi-allelic, thus, representing different alternate alleles that arose in different populations, each with a potentially different biological effect. To be able to understand how the genetic and environmental architecture of complex traits differs between All of Us ethnic groups we need workflows in the Researcher Workbench that can model diverse sources of genetic variation from variance component models to genome-wide association with and without environmental interactions. To achieve this understanding, we propose three aims. In Aim 1 we develop models that can incorporate multiple traits, multiple exposures, and multiple ethnic strata to be able to quantify the trait genetic and environmental architecture within and between ethnic groups. In Aim 2 we develop and implement rigorously tested workflows for the tools developed in Aim 1 into the All of Us Researcher Workbench. The workflows will be supported by with extensive training materials that will include video tutorials, user manuals, and example data sets and instructions how to analyze them. In Aim 3 we apply our All of Us Researcher Workbench workflows to investigate the genetic and environmental architecture of cardiometabolic traits across All of Us ethnic groups. These traits will include lipids, glucose, blood pressure and BMI. Environmental exposures will include smoking, education, and physical activity. Our Researcher Workbench workflows will enable researchers to apply the same models to the extensive list of clinical phenotypes and exposures available in All of Us to address sources of important health disparities.