Fig. 1: Directed Acyclic Graph (DAG) illustrating the complex relationship between exposure and outcome.

Gj represents genetic instrument j with an effect βj on exposure X. Exposure X is associated with outcome Y through K possible pathways of mediation or confounding denoted through the various X1...XK elements. The associations between the main exposure and the various elements denoted by the π arrows purposely do not show directionality to allow for both mediators and confounders. The causal effects on outcome Y are denoted by α1, α2, . . . , αK.