Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization

Wen Zhou, Geoffrey Liu, Rayjean J Hung, Philip C Haycock, Melinda C Aldrich, Angeline S. Andrew, Susanne M. Arnold, Heike Bickeböller, Stig E Bojesen, Paul Brennan, Hans Brunnström, Olle Melander, Neil E Caporaso, Maria Teresa Landi, Chu Chen, Gary E Goodman, David C Christiani, Angela Cox, John K Field, Mikael JohanssonLambertus A Kiemeney, Stephen Lam, Philip Lazarus, Loïc Le Marchand, Gad Rennert, Angela Risch, Matthew B. Schabath, Sanjay Shete, Adonina Tardon, Shanbeh Zienolddiny, Hongbing Shen*, Christopher I. Amos*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample 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-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
Original languageEnglish
Number of pages10
JournalInternational Journal of Cancer
Early online date11 Sep 2020
Publication statusPublished - 23 Sep 2020


  • body mass index
  • causal relationship
  • lung cancer
  • Mendelian randomization
  • smoking phenotypes


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