Fig. 6.

Potential violations of the InSIDE assumption. Top panel pleiotropic effects act directly on the outcome (InSIDE satisfied); middle panel pleiotropic effects act on the outcome via single confounder (InSIDE violated); bottom panel pleiotropic effects act on the outcome via different confounders (InSIDE still violated). Arrows from the genetic variants to the risk factor may not be present for all variants; some variants may affect the confounder directly and not the risk factor. Notation: G ₁, G ₂, …, G _J, genetic variants; X, risk factor; Y, outcome; U, confounder. Pleiotropic effects are signified by curved arrows