Robust inference in summary data Mendelian randomisation via the zero modal pleiotropy assumption

Fernando Hartwig*, George Davey Smith, Jack Bowden

*Corresponding author for this work

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

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Background: Mendelian randomisation (MR) is being increasingly used to strengthen causal inference in observational studies. Availability of summary data of genetic associations for a variety of phenotypes from large genome-wide association studies (GWAS) allows straightforward application of MR using summary data methods, typically in a two-sample design. In addition to the conventional inverse variance weighting (IVW) method, recently developed summary data MR methods, such as the MR-Egger and weighted median approaches, allow a relaxation of the instrumental variable assumptions.
Methods: Here, a new method –the mode-based estimate (MBE) – is proposed to obtain a single causal effect estimate from multiple genetic instruments. The MBE is consistent when the largest number of similar (identical in infinite samples) individual-instrument causal effect estimates comes from valid instruments, even if the majority of instruments are invalid. We evaluate the performance of the method in simulations designed to mimic the two-sample summary data setting, and demonstrate its use by investigating the causal effect of plasma lipid fractions and urate levels on coronary heart disease risk.
Results: The MBE presented less bias and type-I error rates than other methods under the null in many situations. Its power to detect a causal effect was smaller compared to the IVW and weighted median methods, but was larger than that of MR-Egger regression, with sample size requirements typically smaller than those available from GWAS consortia.
Conclusions: The MBE relaxes the instrumental variable assumptions, and should be used in combination with other approaches in a sensitivity analysis.
Original languageEnglish
Article numberdyx102
Pages (from-to)1985-1998
Number of pages14
JournalInternational Journal of Epidemiology
Issue number6
Early online date12 Jul 2017
Publication statusPublished - 1 Dec 2017


  • Causality
  • Instrumental variables
  • Genetic variation
  • Mendelian randomization
  • Genetic pleiotropy


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  • Jack Bowden fellowship transfer

    Gaunt, L. F.


    Project: Research

  • MRC UoB UNITE Unit - Programme 1

    Davey Smith, G.


    Project: Research

  • IEU Theme 3

    Windmeijer, F., Tilling, K. M. & Tilling, K. M.


    Project: Research

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