Comorbid cardiovascular disease in people with severe mental disorders is a major public health concern and poses a considerable financial burden on European Health Care. The CoMorMent project will uncover mechanisms underlying the higher incidence of cardiovascular disease in people with mental disorders. This project builds on our recent findings that genetic variation that affects genes expressed in the brain and which increase the risk of mental disorders also impact lifestyle and behaviour (e.g. diet, exercise, and smoking) that increase cardiovascular risk. The project will identify molecular mechanisms common to mental disorders and unhealthy lifestyles that increase the risk of cardiovascular disease. We will take advantage of our genotyped biobank samples united with large national registries with information about disease trajectories and comorbidity in over 1.8 million people. The “big data” available to CoMorMent means that we can apply new statistical tools to discover novel sequence variants conferring risk of both mental disorders and cardiovascular diseases and determine how these may be mediated by lifestyle or behaviour. We will characterize the underlying mechanisms by identifying accompanying structural brain changes and body fat composition from MRI data in combination with gene expression and functional studies. The CoMorMent multidisciplinary expert team in clinical science (cardiology, psychiatry), genetic epidemiology, molecular genetics, and neuroscience combined with experts in machine learning and computation will generate findings that will form the basis of novel stratification and prediction tools, which will be tested and validated in clinical samples. Thus, CoMorMent will form the basis for a new approach in clinical studies by providing precision medicine tools for clinical implementation to remediate a major public health issue.