Sensitivity Analyses for Robust Causal Inference from Mendelian Randomization Analyses with Multiple Genetic Variants

TLDR

Mendelian randomization studies are increasingly powerful thanks to large GWAS and summarized data, yet using multiple variants from different gene regions makes it unlikely that all satisfy instrumental variable assumptions, so simple IV analyses alone should not be relied upon. This article discusses a range of sensitivity analyses that can support or question the validity of causal inference from Mendelian randomization with multiple genetic variants. We focus on sensitivity analyses that are practically relevant and can be performed with summarized data to ensure robust causal inferences. Mendelian randomization studies with many variants that lack such sensitivity analyses should be treated with skepticism.

Abstract

Mendelian randomization investigations are becoming more powerful and simpler to perform, due to the increasing size and coverage of genome-wide association studies and the increasing availability of summarized data on genetic associations with risk factors and disease outcomes. However, when using multiple genetic variants from different gene regions in a Mendelian randomization analysis, it is highly implausible that all the genetic variants satisfy the instrumental variable assumptions. This means that a simple instrumental variable analysis alone should not be relied on to give a causal conclusion. In this article, we discuss a range of sensitivity analyses that will either support or question the validity of causal inference from a Mendelian randomization analysis with multiple genetic variants. We focus on sensitivity analyses of greatest practical relevance for ensuring robust causal inferences, and those that can be undertaken using summarized data. Aside from cases in which the justification of the instrumental variable assumptions is supported by strong biological understanding, a Mendelian randomization analysis in which no assessment of the robustness of the findings to violations of the instrumental variable assumptions has been made should be viewed as speculative and incomplete. In particular, Mendelian randomization investigations with large numbers of genetic variants without such sensitivity analyses should be treated with skepticism.