Interpreting findings from Mendelian randomization using the MR-Egger method

TLDR

Mendelian randomization‑Egger (MR‑Egger) is a summarized‑data method that tests for directional pleiotropy, estimates causal effects, and relaxes the standard instrumental variable assumptions by relying on the InSIDE assumption. We critically assess the implementation and interpretation of MR‑Egger. MR‑Egger can be biased and inflate Type 1 error due to violations of InSIDE and outlying variants, and we illustrate scenarios where its estimates differ from conventional MR and discuss how to interpret such findings. These issues can seriously compromise causal inferences drawn from MR‑Egger.

Abstract

Mendelian randomization-Egger (MR-Egger) is an analysis method for Mendelian randomization using summarized genetic data. MR-Egger consists of three parts: (1) a test for directional pleiotropy, (2) a test for a causal effect, and (3) an estimate of the causal effect. While conventional analysis methods for Mendelian randomization assume that all genetic variants satisfy the instrumental variable assumptions, the MR-Egger method is able to assess whether genetic variants have pleiotropic effects on the outcome that differ on average from zero (directional pleiotropy), as well as to provide a consistent estimate of the causal effect, under a weaker assumption—the InSIDE (INstrument Strength Independent of Direct Effect) assumption. In this paper, we provide a critical assessment of the MR-Egger method with regard to its implementation and interpretation. While the MR-Egger method is a worthwhile sensitivity analysis for detecting violations of the instrumental variable assumptions, there are several reasons why causal estimates from the MR-Egger method may be biased and have inflated Type 1 error rates in practice, including violations of the InSIDE assumption and the influence of outlying variants. The issues raised in this paper have potentially serious consequences for causal inferences from the MR-Egger approach. We give examples of scenarios in which the estimates from conventional Mendelian randomization methods and MR-Egger differ, and discuss how to interpret findings in such cases.