Introduction to Mendelian randomization.

Abstract

Mendelian randomization (MR), i.e. instrumental variable analysis using genetic instruments, is an approach that incorporates population genetics to improve causal inference. Given that genetics are randomly allocated at conception, this resembles the randomization process in randomized controlled trials and hence is more resistant to unobserved confounding compared to conventional observational studies (e.g. cohort studies). The seminar paper briefly described the origin of MR and its underlying assumptions (relevance, independence, and exclusion restriction). This was followed by introducing one sample MR designs (in which instrument-exposure and instrument-outcome associations are derived from the same sample) and one sample MR design (in which instrument-exposure and instrument-outcome associations are derived from different samples). The seminar paper then summarized key aspects of MR studies, such as instrument selection, data sources for conducting MR studies, and statistical analyses. Variations of MR design were also introduced, such as how this design can inform the effect of drug targets (drug target MR). The STROBE-MR checklist and relevant MR guidelines were introduced. The seminar paper concluded by discussing the credibility crisis of MR studies.