AbstractPatients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.