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We used two\u2010sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome\u2010wide association studies (GWASs) analysis of lung cancer in 29\u2009266 cases and 56\u2009450 controls. We observed a positive causal effect for high BMI on occurrence of small\u2010cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24\u20102.06,\n                    <jats:italic>P<\/jats:italic>\n                    =\u20092.70\u2009\u00d7\u200910\n                    <jats:sup>\u22124<\/jats:sup>\n                    ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR\n                    <jats:sub>MVMR<\/jats:sub>\n                    =\u20091.28, 95% CI = 1.06\u20101.55,\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>MVMR<\/jats:sub>\n                    =\u2009.011), and an inverse effect on lung adenocarcinoma (OR\n                    <jats:sub>MVMR<\/jats:sub>\n                    =\u20090.86, 95% CI = 0.77\u20100.96,\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>MVMR<\/jats:sub>\n                    =\u2009.008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR\n                    <jats:sub>UVMR<\/jats:sub>\n                    =\u20091.19, 95% CI = 1.01\u20101.40,\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>UVMR<\/jats:sub>\n                    =\u2009.036), but this effect disappeared after adjustment of smoking (OR\n                    <jats:sub>MVMR<\/jats:sub>\n                    =\u20091.02, 95% CI = 0.90\u20101.16,\n                    <jats:italic>P<\/jats:italic>\n                    <jats:sub>MVMR<\/jats:sub>\n                    =\u2009.746). These results highlight the histology\u2010specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.\n                  <\/jats:p>","DOI":"10.1002\/ijc.33292","type":"journal-article","created":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T12:57:28Z","timestamp":1600865848000},"page":"1077-1086","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":159,"title":["Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization"],"prefix":"10.1002","volume":"148","author":[{"given":"Wen","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical University  Nanjing China"},{"name":"Institute for Clinical and 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