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Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.78 Figure 1 Instrumental variable analysis to generate causal estimates through Mendelian randomization Figure 1 | Instrumental variable analysis to generate causal estimates through Mendelian randomization. The three principles of instrumental variable analysis are: the instrumental variable (in this case a genetic variant either in isolation or in combination with other variants) must associate with the exposure; the instrumental variable must not associate with confounders that are either known or unknown (U); and there is no pathway from the single nucleotide polymorphism (SNP) to disease that does not include the exposure of interest. This figure is a schematic representation and should not be interpreted as a formal directed acyclic graph. Holmes, M. V. et al. (2017) Mendelian randomization in cardiometabolic disease: challenges in evaluating causality Nat. Rev. Cardiol. doi:10.1038/nrcardio.2017.78