Addressing the credibility crisis in Mendelian randomization

Abstract

Background: Genome-wide association studies have enabled Mendelian randomization analyses to be performed at an industrial scale. Two-sample summary data Mendelian randomization analyses can be performed using publicly available data by anyone who has access to the internet. While this has led to many insightful papers, it has also fuelled an explosion of poor-quality Mendelian randomization publications, which threatens to undermine the credibility of the whole approach.

Findings: We detail five pitfalls in conducting a reliable Mendelian randomization investigation: (1) inappropriate research question, (2) inappropriate choice of variants as instruments, (3) insufficient interrogation of findings, (4) inappropriate interpretation of findings, and (5) lack of engagement with previous work. We have provided a brief checklist of key points to consider when performing a Mendelian randomization investigation; this does not replace previous guidance, but highlights critical analysis choices. Journal editors should be able to identify many low-quality submissions and reject papers without requiring peer review. Peer reviewers should focus initially on key indicators of validity; if a paper does not satisfy these, then the paper may be meaningless even if it is technically flawless.

Conclusions: Performing an informative Mendelian randomization investigation requires critical thought and collaboration between different specialties and fields of research.

Keywords: Bias evaluation; Causal inference; Evidence synthesis; Genetic epidemiology; Instrumental variables; Risk of bias.

Fig. 1

Key considerations when assessing the credibility of a Mendelian randomization investigation

Fig. 2

Genetic associations with an exposure variable that is downstream of a mediating biomarker (diagrams A and B), or has a downstream effect on either a mediating biomarker (diagram C) or a non-causal biomarker (diagram D). In case A, the only causal pathway from the genetic variants to the outcome passes via the exposure; hence, this is an example of “vertical pleiotropy”, and the genetic variants are valid instruments. In case B, there is a causal pathway from the genetic variants to the outcome that does not pass via the exposure; hence, this is an example of “horizontal pleiotropy”, and the genetic variants are not valid instruments. In cases C and D (which also represent “vertical pleiotropy”), Mendelian randomization analyses should be conceptualized in terms of the exposure (the putative causal trait), even if measured genetic associations are expressed in terms of the biomarker. Diagram D is likely to represent the situation between genetic variants in the IL6R gene region, interleukin 6 signalling (exposure), and C-reactive protein (non-causal biomarker). C-reactive protein is likely to be a non-causal biomarker when considering the effect of interleukin 6 receptor inhibition on coronary heart disease [36]