Figure 4.

Comparison between cis- versus trans-Mendelian randomization (MR) for drug target validation. (A) cis-MR variant in cis-single-nucleotide polymorphism (SNP1) in the proximity of gene G₁ is used as an instrument for the protein of interest (P1), which is causally linked to a disease. SNP1 is also associated with P2 (a mediator of the effect of P1 on a disease) and with P3 (a bystander protein residing off the causal pathway from P1 to disease. SNP1 is associated with P1, P2, and P3 and the disease outcome and is a valid instrument for P1. (B) Trans-MR with no horizontal pleiotropy. A variant in another gene (SNP4), which influences expression of P4, upstream in the causal pathway, is used as a trans instrument for P1. SNP4 associates with P4, P1, P2, and P3 and is a valid instrument for P1 because there is no direct causal pathway from P4 to disease. (C) Trans-MR with horizontal pleiotropy. In this scenario, P1 is not causal for disease but is a bystander protein. SNP4 is upstream of P1 and associates with disease because of a direct pathway through P4 (which may not have been measured). As in scenario B SNP4 associates with P1, P2, and P3 and disease, but it is not a valid instrument for P1 because there is a direct causal pathway from P4 to disease. (Figure reprinted from Schmidt et al. 2020, courtesy of a Creative Commons Attribution 4.0 International License.)