The method estimates a putative causal effect of the exposure on the outcome (bxy) as a function of the relationship between the SNPs’ effects on the exposure (bzx) and the SNPs’ effects on the outcome (bzy), given the assumption that the effect of non-pleiotropic SNPs on an exposure (x) should be related to their effect on the outcome (y) in an independent sample only via mediation through the phenotypic causal pathway (bxy). The estimated causal effect coefficients (bxy) are approximately equal to the natural log odds ratio (OR) for a case-control trait29. An OR of 2 can be interpreted as a doubled risk compared to the population prevalence of a binary trait for every SD increase in the exposure trait. For quantitative traits the bxy can be interpreted as a one standard deviation increase explained in the outcome trait for every SD increase in the exposure trait. This method can help differentiate the likely causal direction of association between two traits but cannot make any statement about the intermediate mechanisms involved in any potential causal process.
