Cardiotoxicity of commonly prescribed medications, typically assessed by electrocardiographic features such as prolongation of the QT interval, has regulatory effects and is associated with potentially fatal outcomes. This project aims to advance understanding of the genetic basis for drug cardiotoxicity and its downstream consequences by leveraging the extensive data resources of the Kaiser Permanente Northern California Research Program on Genes, Environment and Health (RPGEH), and the ability to link these data to other health plan databases, namely Kaiser Permanente Northern California’s pharmacy, electrocardiogram, and outpatient/inpatient utilization databases. Longitudinal analyses of the QT interval over up to 20 years will be conducted in the large and ethnically diverse Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort of the RPGEH. Genetic loci that influence adverse drug reactions will be identified and characterized, and the associated biological pathways and tissues will be investigated. This study will also examine: a) genetic predictors of adverse outcomes (e.g., ventricular arrhythmias and Torsade de Pointes), b) whether the identified gene-by-drug interactions are associated with these adverse outcomes, and c) degree of mediation by QTc prolongation.