烟草吸烟被认为是结直肠癌（CRC）的一个危险因素，但该复杂关系和潜在途径尚未完全理解。我们进行了两代Mendelian randomisation（MR）分析，使用吸烟行为和血液中相关DNA甲基化的遗传工具，并结合结直肠癌的汇总水平GWAS数据来解开这种关系。我们还进行了共同定位分析和前瞻性基因-环境相互作用分析作为验证。在单变量MR分析中，我们找到了吸烟开始对CRC风险的致病影响的令人信服的证据，并观察到了吸烟戒断对CRC风险的保护作用的暗示性证据。多元MR分析显示，这些关联与其他吸烟表型和饮酒无关。我们发现，在CpG位点cg17823346 【ZMIZ1】的遗传预测甲基化会降低CRC风险；而在cg02149899的遗传预测甲基化则会增加CRC风险。共定位和基因-环境相互作用分析进一步证实了cg17823346 【ZMIZ1】和cg02149899的表观修饰与CRC风险之间的关系。我们的研究确认了烟草吸烟、DNA甲基化与CRC风险之间的显著关联，并为烟草吸烟对CRC风险的致病效应提供了新的见解。© 2023年。作者。

Tobacco smoking is suggested as a risk factor for colorectal cancer (CRC), but the complex relationship and the potential pathway are not fully understood.We performed two-sample Mendelian randomisation (MR) analyses with genetic instruments for smoking behaviours and related DNA methylation in blood and summary-level GWAS data of colorectal cancer to disentangle the relationship. Colocalization analyses and prospective gene-environment interaction analyses were also conducted as replication.Convincing evidence was identified for the pathogenic effect of smoking initiation on CRC risk and suggestive evidence was observed for the protective effect of smoking cessation in the univariable MR analyses. Multivariable MR analysis revealed that these associations were independent of other smoking phenotypes and alcohol drinking. Genetically predicted methylation at CpG site cg17823346 [ZMIZ1] were identified to decrease CRC risk; while genetically predicted methylation at cg02149899 would increase CRC risk. Colocalization and gene-environment interaction analyses added further evidence to the relationship between epigenetic modification at cg17823346 [ZMIZ1] as well as cg02149899 and CRC risk.Our study confirms the significant association between tobacco smoking, DNA methylation and CRC risk and yields a novel insight into the pathogenic effect of tobacco smoking on CRC risk.© 2023. The Author(s).