Background <p>Age-related diseases, including Parkinson’s disease and gastric cancer, substantially affect the global aging population. Previous observational research has suggested a potential association between Parkinson’s disease and gastric cancer; however, findings regarding this aspect have been inconsistent. In the present study, we used data from genome-wide association studies to infer a causal relationship between Parkinson’s disease and gastric cancer based on genetic variations.</p> Methods <p>We used the two-sample Mendelian randomization method to analyze data from the genome-wide association study catalog, including 482,730 and 476,116 patients with Parkinson’s disease and gastric cancer, respectively. Inverse-variance weighting was used as the primary Mendelian randomization analysis. We conducted sensitivity analyses to evaluate heterogeneity and pleiotropy, followed by two-step Mendelian randomization to ascertain the latent mediator of the relationship between Parkinson’s disease and gastric cancer.</p> Results <p>Our results suggested a causal negative relationship between Parkinson’s disease and gastric cancer. Heterogeneity and pleiotropy analyses confirmed the robustness of the inverse-variance weighting results. Furthermore, P2X6 was identified as a key factor mediating this negative causal relationship.</p> Conclusions <p>Patients with Parkinson’s disease may have a lower risk of developing gastric cancer, with P2X6 serving as a significant mediating variable. These novel insights can aid the development of potential therapeutic targets for patients with Parkinson’s disease or gastric cancer.</p>