A framework for exploiting horizontal pleiotropy. If a SNP appears to be an outlier in an MR analysis, then it is hypothesised that it is additionally associating with the outcome through another trait. Searching through GWAS databases to find candidate traits, then modelling the original exposure-outcome association accounting for the candidate traits allows a) detection of new putative risk factors and b) reducing heterogeneity and/or bias in the original estimate.
Depends on the ability to accurately estimate the effect estimates on the path through candidate traits. Automated using available GWAS databases such as MR-Base, which do not have complete coverage of the human phenome and therefore unlikely to be able to completely account for the heterogeneity.
- Cho Y, Haycock PC, Gaunt TR et al. MR-TRYX: Exploiting horizontal pleiotropy to infer novel causal pathways. bioRxiv 2018;doi: http://dx.doi.org/10.1101/476085.