AbstractConsidering the high prevalence and poor prognosis of cardiometabolic multimorbidity (CMM), identifying causal factors and actively implementing preventive measures is crucial. However, Mendelian randomization (MR), a key method for identifying the causal factors of CMM, requires knowledge of the effects of SNPs on CMM, which remain unknown. We first analyzed the genetic overlap of single cardiometabolic diseases (CMDs) using the latest genome‐wide association study (GWAS) for evidential support and comparison. We observed strong positive genetic correlations and shared loci among all CMDs. Further, GWAS and post‐GWAS analyses of CMM were performed in 407 949 European ancestry individuals from the UK Biobank. Eleven loci and 12 lead SNPs were identified. By comparison, we found these SNPs were a subset of SNPs associated with CMDs, including both shared and non‐shared SNPs. Then, the polygenic risk score model predicted the risk of CMM (C‐index = 0.62) and we identified candidate genes related to lipid metabolism and immune function. Finally, as an example, two‐sample MR analysis based on the GWAS revealed potential causal effects of total cholesterol, serum urate, body mass index, and smoking on CMM. These results provide a basis for future MR research and inspire future studies on the mechanism and prevention of CMM.