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

Research output: Contribution to journalArticle


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.


  • 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
  • Neil E. Caporaso
  • Maria Teresa Landi
  • Chu Chen
  • Gary E. Goodman
  • David C. Christiani
  • Angela Cox
  • John K. Field
  • Mikael Johansson
  • Lambertus A. Kiemeney
  • Stephen Lam
  • Philip Lazarus
  • Loïc Le Marchand
  • Gad Rennert
  • Angela Risch
  • Matthew B. Schabath
  • Sanjay S. Shete
  • Adonina Tardón
  • Shanbeh Zienolddiny
  • Hongbing Shen
  • Christopher I. Amos
External organisations
  • Nanjing Medical University
  • Baylor College of Medicine
  • Princess Margaret Hospital University of Toronto
  • Sinai Health System
  • University of Toronto
  • University of Bristol
  • Vanderbilt University
  • Dartmouth College
  • University of Kentucky Medical Center
  • University Medical Center Göttingen
  • International Agency for Research on Cancer, World Health Organization
  • National Cancer Institute, NCI
  • University of Washington
  • University of Sheffield
  • University of Liverpool
  • Umeå University
  • Radboud University Medical Center
  • British Columbia Cancer Agency
  • Washington State University
  • H. Lee Moffitt Cancer Center & Research Institute
  • University of Texas MD Anderson Cancer Center
  • National Institute of Occupational Health, Norway
  • Copenhagen University Hospital
  • Harvard T.H. Chan School of Public Health
  • University of Hawaii Cancer Center
  • Technion - Israel Institute of Technology
  • University of Salzburg
  • German Cancer Research Centre
  • University Hospital Heidelberg
  • German Center for Lung Research (DZL)
  • University of Oviedo
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology


  • body mass index, causal relationship, lung cancer, Mendelian randomization, smoking phenotypes
Original languageEnglish
Pages (from-to)1077-1086
JournalInternational Journal of Cancer
Issue number5
Early online date2020 Sep 11
Publication statusPublished - 2021
Publication categoryResearch