An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings

Eleanor Sanderson, George Davey Smith, Frank Windmeijer, Jack Bowden

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

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Background: Mendelian randomization (MR) is a powerful tool in epidemiology that can be used to estimate the causal effect of an exposure on an outcome in the presence of unobserved confounding, by utilizing genetic variants that are instrumental variables (IVs) for the exposure. This has been extended to multivariable MR (MVMR) to estimate the effect of two or more exposures on an outcome. 

Methods and results: We use simulations and theory to clarify the interpretation of estimated effects in a MVMR analysis under a range of underlying scenarios, where a secondary exposure acts variously as a confounder, a mediator, a pleiotropic pathway and a collider. We then describe how instrument strength and validity can be assessed for an MVMR analysis in the single-sample setting, and develop tests to assess these assumptions in the popular two-sample summary data setting. We illustrate our methods using data from UK Biobank to estimate the effect of education and cognitive ability on body mass index. 

Conclusion: MVMR analysis consistently estimates the direct causal effect of an exposure, or exposures, of interest and provides a powerful tool for determining causal effects in a wide range of scenarios with either individual- or summary-level data.

Original languageEnglish
Article numberdyy262
Pages (from-to)713-727
Number of pages15
JournalInternational Journal of Epidemiology
Issue number3
Early online date10 Dec 2018
Publication statusPublished - 10 Dec 2018

Structured keywords

  • ECON CEPS Health
  • ECON Applied Economics


  • Cochran's Q statistic
  • instrument strength
  • instrument validity
  • Mendelian randomization
  • multivariable Mendelian randomization
  • two-sample Mendelian randomization


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