Simple SummaryAs lifestyle intervention has come to the fore for cancer prevention, the causal effect of lifestyle behaviors on prostate cancer remains to be elucidated. No comparison across different ethnicities has been conducted previously. In this study, we used a novel instrumental variable methodology, namely, Mendelian randomization analysis, to explore the associations between a wide range of behavioral factors and prostate cancer in both Europeans and East Asians. The results of this study showed that lifetime tobacco smoking was positively related to an increased prostate cancer risk in Europeans. In East Asians, alcohol consumption and delayed sexual initiation were risk factors, while vegetable intake was a protective factor for prostate cancer. These findings largely broaden the evidence base for the spectrum of risk factors for prostate cancer, and provide insights into the priority of behavioral interventions for high-risk groups in different population settings.AbstractObjective: Early evidence is disputable for the effects of modifiable lifestyle behaviors on prostate cancer (PCa) risk. No research has yet appraised such causality in different ancestries using a Mendelian randomization (MR) approach. Methods: A two-sample univariable and multivariable MR analysis was performed. Genetic instruments associated with lifestyle behaviors were selected based on genome-wide association studies. Summary-level data for PCa were obtained from PRACTICAL and GAME-ON/ELLIPSE consortia for Europeans (79,148 PCa cases and 61,106 controls), and ChinaPCa consortium for East Asians (3343 cases and 3315 controls). Replication was performed using FinnGen (6311 cases and 88,902 controls) and BioBank Japan data (5408 cases and 103,939 controls). Results: Tobacco smoking was identified as increasing PCa risks in Europeans (odds ratio [OR]: 1.95, 95% confidence interval [CI]: 1.09–3.50,p= 0.027 per standard deviation increase in the lifetime smoking index). For East Asians, alcohol drinking (OR: 1.05, 95%CI: 1.01–1.09,p= 0.011) and delayed sexual initiation (OR: 1.04, 95%CI: 1.00–1.08,p= 0.029) were identified as risk factors, while cooked vegetable consumption (OR: 0.92, 95%CI: 0.88–0.96,p= 0.001) was a protective factor for PCa. Conclusions: Our findings broaden the evidence base for the spectrum of PCa risk factors in different ethnicities, and provide insights into behavioral interventions for prostate cancer.