A genetic risk score could be beneficial in assisting clinical diagnosis for complex diseases with high heritability. With large-scale genome-wide association (GWA) data, the current study constructed a genetic risk model with a machine learning approach for bipolar disorder (BPD). The GWA dataset of BPD from the Genetic Association Information Network was used as the training data for model construction, and the Systematic Treatment Enhancement Program (STEP) GWA data were used as the validation dataset. A random forest algorithm was applied for pre-filtered markers, and variable importance indices were assessed. 289 candidate markers were selected by random forest procedures with good discriminability; the area under the receiver operating characteristic curve was 0.944 (0.935-0.953) in the training set and 0.702 (0.681-0.723) in the STEP dataset. Using a score with the cutoff of 184, the sensitivity and specificity for BPD was 0.777 and 0.854, respectively. Pathway analyses revealed important biological pathways for identified genes. In conclusion, the present study identified informative genetic markers to differentiate BPD from healthy controls with acceptable discriminability in the validation dataset. In the future, diagnosis classification can be further improved by assessing more comprehensive clinical risk factors and jointly analysing them with genetic data in large samples.