*Geek Box: Mendelian Randomisation

*Geek Box: Mendelian Randomisation

Mendelian randomisation [MR] is a principle of using genetics to mimic a long-term randomised controlled trial, particularly where a long-term intervention study may be unethical or practically infeasible. Because an individuals’ genes are ‘assigned’ when they are conceived, this in effect it is the purest form of randomisation, i.e., the genetic lottery from Mom and Pops.

Well-conducted MR can provide an unconfounded estimate of the relationship between an exposure and an outcome. It is unconfounded because the genetic variant results in a certain physiological response that is independent of other considerations. Thus, to be properly conducted, a MR study has to satisfy three criteria:

  1. The genetic variant must be associated with the specific mediating factor, e.g., LDL-C or TMAO;
  2. The genetic variant must not be associated with any potential confounders that could influence the outcome, and;
  3. The genetic variant must only influence the disease outcome through the specific mediating factor, not through other mechanisms.

In keeping with this study example, the genetic variants examined were those associated with increased gut microbiota-dependent metabolites, i.e., TMAO, that also did not potentially influence disease risk by other pathways. Similarly with LDL-C, the genetic variants examined are those that specifically influence cholesterol clearance from the blood. When long-term randomised studies are not possible, Mendelian randomisation is a powerful tool to examine potential cause-effect relationships.