Mendelian Randomization versus Path Models: Making Causal Inferences in Genetic Epidemiology

Objective: The term Mendelian randomization is popular in the current literature. The first aim of this work is to describe the idea of Mendelian randomization studies and the assumptions required for drawing valid conclusions. The second aim is to contrast Mendelian randomization and path modeling when different 'omics' levels are considered jointly. Methods: We define Mendelian randomization as introduced by Katan in 1986, and review its crucial assumptions. We introduce path models as the relevant additional component to the current use of Mendelian randomization studies in 'omics'. Real data examples for the association between lipid levels and coronary artery disease illustrate the use of path models. Results: Numerous assumptions underlie Mendelian randomization, and they are difficult to be fulfilled in applications. Path models are suitable for investigating causality, and they should not be mixed up with the term Mendelian randomization. In many applications, path modeling would be the appropriate analysis in addition to a simple Mendelian randomization analysis. Conclusions: Mendelian randomization and path models use different concepts for causal inference. Path modeling but not simple Mendelian randomization analysis is well suited to study causality with different levels of 'omics' data.