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Background:  Polygenic risk score (PRS) is widely regarded as a predictor of genetic susceptibility to disease, applied to individuals to predict the risk of disease occurrence. When the gene-environment (G×E) interaction is considered, the traditional PRS prediction model directly uses PRS to interact with the environment without considering the interactions between each variant and environment, which may lead to prediction performance and risk stratification of complex diseases are not promising.   Methods:  We developed a method called interaction PRS (iPRS), reconstructing PRS by leveraging G×E interactions. Two extensive simulations evaluated prediction performance, risk stratification, and calibration performance of the iPRS prediction model, and compared it with the traditional PRS prediction model. Real data analysis was performed using existing data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial study to predict genetic susceptibility, pack-years of smoking history, and G×E interactions in patients with lung cancer.   Results:  Two extensive simulations indicated iPRS prediction model could improve the prediction performance of disease risk, the accuracy of risk stratification, and clinical calibration performance compared with the traditional PRS prediction model, especially when antagonism accounted for the majority of the interaction. PLCO real data analysis also suggested that the iPRS prediction model was superior to the PRS prediction model in predictive effect ( p  = 0.0205).   Conclusion:  IPRS prediction model could have a good application prospect in predicting disease risk, optimizing the screening of high-risk populations, and improving the clinical benefits of preventive interventions among populations.

IPRS: Leveraging Gene-Environment Interaction to Reconstruct Polygenic Risk Score