MR is an extension of epidemiological causal models (for review see: (Davey Smith and Hemani, 2014, Holmes et al., 2014)). Assume that two traits are correlated - such as body mass index (A) and cardiovascular disease (B) - and that it is reasonable to hypothesize that A causes B. If one could identify genetic variants, including single loci, or multiple variants that comprise a PRS, that are robustly associated with A, but have no independent effects on B [although, methods that adjust for such pleiotropy exist (Bowden et al., 2015)] or on any covariate (e.g., smoking) related to B, then such a PRS might serve as a “genetic instrument” for MR analyses. If BMI PRS predict cardiovascular disease, indirectly through BMI, then such an association may be viewed as evidence in favor of causation (i.e., higher BMI results in cardiovascular disease) (Holmes et al., 2014). In an empirical test of this hypothesis, one study found that BMI PRS (discovery N = 108, 912) predicted cardiometabolic traits and outcomes, but not coronary artery disease, in an independent cohort of 34, 538
