AbstractThe proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never‐smoking women. We first performed a large GWAS meta‐analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never‐smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta‐analysis identified eight known loci and a novel locus (5q11.2) at the genome‐wide statistical significance level of P < 5 × 10⁻⁸. Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS‐21) for lung cancer in never‐smoking women. Furthermore, PRS‐21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18‐1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00‐1.72) and high (HR = 2.09, 95% CI: 1.56‐2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS‐21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS‐derived PRS‐21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never‐smoking Asian women, demonstrating the potential for identification of high‐risk individuals and early screening.