Severe asthma is a chronic inflammatory airway disease with great therapeutic challenges. Understanding the genetic and molecular mechanisms of severe asthma may help identify therapeutic strategies for this complex condition. RNA expression data were analyzed using a combination of artificial intelligence methods to identify novel genes related to severe asthma. Through the ANOVA feature selection approach, 100 candidate genes were selected among 54,715 mRNAs in blood samples of patients with severe asthmatic and healthy groups. A deep learning model was used to validate the significance of the candidate genes. The accuracy, F1-score, AUC-ROC, and precision of the 100 genes were 83%, 0.86, 0.89, and 0.9, respectively. To discover hidden associations among selected genes, association rule mining was applied. The top 20 genes including the PTBP1, RAB11FIP3, APH1A, and MYD88 were recognized as the most frequent items among severe asthma association rules. The PTBP1 was found to be the most frequent gene associated with severe asthma among those 20 genes. PTBP1 was the gene most frequently associated with severe asthma among candidate genes. Identification of master genes involved in the initiation and development of asthma can offer novel targets for its diagnosis, prognosis, and targeted-signaling therapy.© 2023. Springer Nature Limited.