DOI: 10.1101/19009605Oct 18, 2019Paper

Exploring and mitigating potential bias when genetic instrumental variables are associated with multiple non-exposure traits in Mendelian randomization

MedRxiv : the Preprint Server for Health Sciences
Qian YangD. A. Lawlor

Abstract

Background: Our aim is to produce guidance on exploring and mitigating possible bias when genetic instrumental variables (IVs) associate with traits other than the exposure of interest in Mendelian randomization (MR) studies. Methods: We use causal diagrams to illustrate scenarios that could result in IVs being related to (non-exposure) traits. We recommend that MR studies explore possible IV-non-exposure associations across a much wider range of traits than is usually the case. Where associations are found, confounding by population stratification should be assessed through adjusting for relevant population structure variables. To distinguish vertical from horizontal pleiotropy we suggest using bidirectional MR between the exposure and non-exposure traits and MR of the effect of the non-exposure traits on the outcome of interest. If vertical pleiotropy is plausible, standard MR methods should be unbiased. If horizontal pleiotropy is plausible, we recommend using multivariable MR to control for observed pleiotropic traits and conducting sensitivity analyses which do not require prior knowledge of specific invalid IVs or pleiotropic paths. Results: We applied our recommendations to an illustrative example of the effect of matern...Continue Reading

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