PROJECT SUMMARY Myocardial infarction (MI) and coronary artery disease (CAD) are the leading causes of death in Western societies. Individuals with CAD are typically asymptomatic, with the first manifestations often being major adverse cardiac events (MACE), such as MI, stroke, or sudden death due to the rupture of an atherosclerotic plaque. However, despite the clinical significance of these thrombotic events, our understanding of the genetic and molecular basis of MI remains incomplete. Furthermore, even though most patients with MI have CAD, not all patients with CAD develop MI. This observation suggests that some of the mechanisms that predispose to MI may be distinct from those that establish and promote atherosclerosis. This concept is supported by the results of our recent multi-national genetics collaboration with >830,000 subjects, which identified several novel loci that were associated specifically or more strongly with MI than CAD. Genomics and bioinformatic analyses implicated SLC44A3 as the causal gene at a previously unrecognized MI-specific locus on chromosome 1p21. In recent follow-up studies, we used a more direct comparative genetics strategy among CAD patients with and without MI (CAD+/MI+ vs CAD+/MI-). These efforts revealed additional genetic factors that were strongly associated with MI but not CAD itself, as well as provided confirmatory evidence for SLC44A3 being a novel MI-specific locus. To our knowledge, SLC44A3 and the other newly identified loci represent the only genetic factors that exhibit this MI-specific association pattern. However, independent replication, prioritization, and functional validation of these observations is still required in order to classify their association signals as being specific for MI and not CAD. Our overall hypothesis, which is supported by substantial preliminary data, is that SLC44A3 and other newly identified positional candidate genes represent genetic risk factors that specifically or more strongly predispose to MI than CAD per se. To validate this hypothesis, we propose a series of integrative genetics, bioinformatics, and functional analyses in humans and mouse models. In Specific Aim 1, we will comprehensively elucidate the genetic landscape of MI in patients with CAD through a combination of large-scale meta-analyses and whole-exome rare variant analyses with multi-ancestry cohorts. Candidate causal genes for MI among CAD patients will be prioritized through integration of robust bioinformatics, fine- mapping, and functional genomics analyses. In Specific Aim 2, we will use a translational in vivo mouse model of plaque rupture to experimentally validate Slc44a3 as an MI-specific susceptibility gene. Taken together, the proposed studies will use innovative and complementary approaches to elucidate the genetic basis of MI among CAD patients, provide functional validation of high probability candidate causal genes in mouse models, and help prioritize novel targets for therapeuti...