Illustration of vertical (A) and horizontal (B) pleiotropy as diagrammed by directed acyclic graphs. Depiction shown for genetic variant G, exposures X1 and X2, outcome Y, confounder of the X1-outcome association U1, and confounder of the X2-outcome association U2. In the vertical pleiotropy case illustrated in A, genetic variant G is associated with exposure X1, which exerts a downstream causal effect on exposure X2, which then exerts a causal effect on outcome Y. In the horizontal pleiotropy case illustrated in B, genetic variant G is associated with exposure X1 and independently associated with unrelated exposure X2, both exposures of which are associated with outcome Y.