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.

中文翻译：

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谨慎检查反向因果关系在孟德尔随机化中的作用

最近，孟德尔随机化 (MR) 作为评估遗传关联研究中表型之间因果关系的概念而广受欢迎。最近开发了标准 MR 方法的扩展，即 MR Steiger 方法，以在前瞻性研究中推断两种表型之间的因果方向。通过模拟研究，我们检查和量化了 MR Steiger 方法确定两种表型之间因果方向（即效应方向）的能力。通过模拟研究，我们的结果表明，MR Steiger 方法可能无法正确识别因果关系的方向。这是真的，尤其是在存在多效性的情况下。我们还将 MR Steiger 方法应用于 COPDGene 研究，这是一项针对当前和以前吸烟者的慢性阻塞性肺病 (COPD) 的病例对照研究，检查吸烟对肺功能的作用。我们在 Github 上创建了一个 R 包，名为reverseDirection为用户指定的场景运行模拟，以检查 MR Steiger 方法何时可以正确确定任何用户指定场景中两个表型之间的因果方向。总之，我们的结果强调了在使用 MR Steiger 方法推断因果关系方向时谨慎的重要性。