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Caution against examining the role of reverse causality in Mendelian Randomization

Sharon M. Lutz, Ann Chen Wu, John E. Hokanson, Stijn Vansteelandt (UGent) and Christoph Lange
(2021) GENETIC EPIDEMIOLOGY. 45(5). p.445-454
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Abstract
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.
Keywords
Genetics(clinical), Epidemiology, causal direction, Mendelian Randomization, reverse causality, GENETIC EPIDEMIOLOGY, CIGARETTE-SMOKING, INSTRUMENTS, DEPRESSION, CAUSATION

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MLA
Lutz, Sharon M., et al. “Caution against Examining the Role of Reverse Causality in Mendelian Randomization.” GENETIC EPIDEMIOLOGY, vol. 45, no. 5, 2021, pp. 445–54, doi:10.1002/gepi.22385.
APA
Lutz, S. M., Wu, A. C., Hokanson, J. E., Vansteelandt, S., & Lange, C. (2021). Caution against examining the role of reverse causality in Mendelian Randomization. GENETIC EPIDEMIOLOGY, 45(5), 445–454. https://doi.org/10.1002/gepi.22385
Chicago author-date
Lutz, Sharon M., Ann Chen Wu, John E. Hokanson, Stijn Vansteelandt, and Christoph Lange. 2021. “Caution against Examining the Role of Reverse Causality in Mendelian Randomization.” GENETIC EPIDEMIOLOGY 45 (5): 445–54. https://doi.org/10.1002/gepi.22385.
Chicago author-date (all authors)
Lutz, Sharon M., Ann Chen Wu, John E. Hokanson, Stijn Vansteelandt, and Christoph Lange. 2021. “Caution against Examining the Role of Reverse Causality in Mendelian Randomization.” GENETIC EPIDEMIOLOGY 45 (5): 445–454. doi:10.1002/gepi.22385.
Vancouver
1.
Lutz SM, Wu AC, Hokanson JE, Vansteelandt S, Lange C. Caution against examining the role of reverse causality in Mendelian Randomization. GENETIC EPIDEMIOLOGY. 2021;45(5):445–54.
IEEE
[1]
S. M. Lutz, A. C. Wu, J. E. Hokanson, S. Vansteelandt, and C. Lange, “Caution against examining the role of reverse causality in Mendelian Randomization,” GENETIC EPIDEMIOLOGY, vol. 45, no. 5, pp. 445–454, 2021.
@article{8710288,
  abstract     = {{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.}},
  author       = {{Lutz, Sharon M. and Wu, Ann Chen and Hokanson, John E. and Vansteelandt, Stijn and Lange, Christoph}},
  issn         = {{0741-0395}},
  journal      = {{GENETIC EPIDEMIOLOGY}},
  keywords     = {{Genetics(clinical),Epidemiology,causal direction,Mendelian Randomization,reverse causality,GENETIC EPIDEMIOLOGY,CIGARETTE-SMOKING,INSTRUMENTS,DEPRESSION,CAUSATION}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{445--454}},
  title        = {{Caution against examining the role of reverse causality in Mendelian Randomization}},
  url          = {{http://doi.org/10.1002/gepi.22385}},
  volume       = {{45}},
  year         = {{2021}},
}
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