Fig. 1.

Framework and assumptions of Mendelian randomization (MR) analyses. In addition to a gene-environment equivalence assumption, MR relies on the following three core assumptions of formal instrumental variable analysis (in addition to those described as the “homogeneity”, “monotonicity” and “no effect modification” assumptions): (1) the “relevance” assumption—the genetic variant(s) being used as an instrument (Z) is robustly associated with the exposure (X); (2) the “independence” or “exchangeability” assumption—there are no common causes of the genetic variant(s) and outcome (e.g., population substructure, assortative mating and dynastic effects); and (3) the “exclusion restriction” assumption—there is no independent pathway between the genetic variant(s) and outcome (Y) other than through the exposure (X)—also known as horizontal pleiotropy