A signature of platelet reactivity in CBC scattergrams reveals genetic predictors of thrombotic disease risk

•PR can be predicted from scattergrams generated by hematology analyzers of a type that is in widespread clinical use.•Genetic analysis of predicted PR reveals associations with the risk of thrombotic diseases, including stroke. [Display omitted] Genetic studies of platelet reactivity (PR) phenotypes may identify novel antiplatelet drug targets. However, these discoveries have been limited by small sample sizes (n < 5000) because of the complexity of measuring the PR. We trained a model to predict the PR using complete blood count (CBC) scattergrams. A genome-wide association study of this phenotype in 29 806 blood donors identified 21 distinct associations implicating 20 genes, of which 6 have been identified previously. The effect size estimates were significantly correlated with estimates from a study of flow-cytometry-measured PR and a study of the phenotype of in vitro thrombus formation. A genetic score of PR built from the 21 variants was associated with myocardial infarction and pulmonary embolism. Mendelian randomization analyses showed that PR was causally associated with the risks of coronary artery disease, stroke, and venous thromboembolism. Our approach provides a blueprint for using phenotype imputation to study the determinants of hard-to-measure but biologically important hematological traits.