ABSTRACT This proposal builds into our ongoing research in genetics and disease risk in admixed Hispanic populations. Hispanics/Latinos are the larger racial/ethnic minority in the U.S. They have a high burden of cardiometabolic and inflammatory related diseases. Genetically, Hispanics are an heterogenous population comprised of multiple ancestral groups (primarily Native American, West African, European) from recent admixture. Few studies have leveraged genetic ancestry to address differences in disease susceptibility. This study will leverage the comprehensive data from the large population-based Hispanic Community Health Study/Study of Latinos for discovery of ancestry-enriched susceptibility loci. We propose to integrate genomics and multi- omics data to map genomic segments and variants inherited from the ancestral population with the higher disease variant frequency (Aim 1), use new approaches for fine-mapping genomic regions (Aim 2), and validate our findings for clinical relevance in Hispanics/Latinos from the All of Us study (Aim 3). We expect to gain insights into the identified ancestry-related genomic regions and variants and their relationship to disease states. This proposal uniquely complements large ongoing genome wide association approaches. Our results may provide insights into differences in disease risk in admixed populations. Ultimately this research could inform personalized medicine and improve public health.