Detecting and correcting for bias in Mendelian randomization analyses using gene-by-environment interactions

Wes Spiller, David Slichter, Jack Bowden, George Davey Smith

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

44 Citations (Scopus)
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Background: Mendelian randomization (MR) has developed into an established method for strengthening causal inference and estimating causal effects, largely due to the proliferation of genome-wide association studies. However, genetic instruments remain controversial as horizontal pleiotropic effects can introduce bias into causal estimates. Recent work has highlighted the potential of gene-environment interactions in detecting and correcting for pleiotropic bias in MR analyses.

Methods: We introduce MR using Gene-by-Environment interactions (MRGxE) as a framework capable of identifying and correcting for pleiotropic bias. If an instrument-covariate interaction induces variation in the association between a genetic instrument and exposure, it is possible to identify and correct for pleiotropic effects. The interpretation of MRGxE is similar to conventional summary MR approaches, with a particular advantage of MRGxE being the ability to assess the validity of an individual instrument.

Results: We investigate the effect of adiposity, measured using body mass index (BMI), upon systolic blood pressure (SBP) using data from the UK Biobank and a single weighted allelic score informed by data from the GIANT consortium. We find MRGxE produces findings in agreement with two-sample summary MR approaches. Further, we perform simulations highlighting the utility of the approach even when the MRGxE assumptions are violated.

Conclusions: By utilising instrument-covariate interactions in Mendelian randomization analyses implemented within a linear regression framework, it is possible to identify and correct for horizontal pleiotropic bias, provided the average magnitude of pleiotropy is constant across interaction covariate subgroups.
Original languageEnglish
Number of pages11
JournalInternational Journal of Epidemiology
Early online date20 Nov 2018
Publication statusE-pub ahead of print - 20 Nov 2018


  • Mendelian randomization
  • invalid instruments
  • pleiotropy
  • MRGxE
  • gene-environment interaction


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