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Interpreting findings from Mendelian randomization using the MR-Egger method

Published version
Peer-reviewed

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Authors

Thompson, SG 

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.

Description

Keywords

instrumental variable, MR-Egger, Mendelian randomization, robust methods, summarized data

Journal Title

European Journal of Epidemiology

Conference Name

Journal ISSN

0393-2990
1573-7284

Volume Title

32

Publisher

Springer
Sponsorship
Wellcome Trust (100114/Z/12/Z)
Medical Research Council (G0700463)
Medical Research Council (MR/L003120/1)
Wellcome Trust (204623/Z/16/Z)
British Heart Foundation (CH/12/2/29428)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
Medical Research Council (G0700463/1)
Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 204623/Z/16/Z). Simon G. Thompson is supported by the British Heart Foundation (Grant Number CH/12/2/ 29428).