AbstractAlthough a few studies have reported the effects of several polymorphisms on major adverse cardiovascular events (MACE) in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI), these genotypes account for only a small fraction of the variation and evidence is insufficient. This study aims to identify new genetic variants associated with MACE end point during the 18-month follow-up period by a two-stage large-scale sequencing data, including high-depth whole exome sequencing of 168 patients in the discovery cohort and high-depth targeted sequencing of 1793 patients in the replication cohort. We discovered eight new genotypes and their genes associated with MACE in patients with ACS, including MYOM2 (rs17064642), WDR24 (rs11640115), NECAB1 (rs74569896), EFR3A (rs4736529), AGAP3 (rs75750968), ZDHHC3 (rs3749187), ECHS1 (rs140410716), and KRTAP10-4 (rs201441480). Notably, the expressions of MYOM2 and ECHS1 are downregulated in both animal models and patients with phenotypes related to MACE. Importantly, we developed the first superior classifier for predicting 18-month MACE and achieved high predictive performance (AUC ranged between 0.92 and 0.94 for three machine-learning methods). Our findings shed light on the pathogenesis of cardiovascular outcomes and may help the clinician to make a decision on the therapeutic intervention for ACS patients.