Caution against examining the role of reverse causality in Mendelian Randomization

Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two ph...

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Bibliographic Details
Published in:Genetic epidemiology Vol. 45; no. 5; pp. 445 - 454
Main Authors: Lutz, Sharon M., Wu, Ann Chen, Hokanson, John E., Vansteelandt, Stijn, Lange, Christoph
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01.07.2021
Subjects:
causal direction
Causality
Chronic obstructive pulmonary disease
Lung diseases
Mendelian Randomization
Obstructive lung disease
Phenotypes
Pleiotropy
Respiratory function
reverse causality
causal direction
reverse causality
Mendelian Randomization
ISSN:0741-0395, 1098-2272, 1098-2272
Online Access:Get full text
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Summary:Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examined and quantified the ability of the MR Steiger approach to determine the causal direction between two phenotypes (i.e., effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case‐control study of chronic obstructive pulmonary disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user‐specified scenarios to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer the direction of causality.
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ISSN:0741-0395
1098-2272
1098-2272
DOI:10.1002/gepi.22385