*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 [see figure, below], 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.

An IV is only valid where the 3 assumptions above hold. This is crucial, because it means that claims of “causality” can only be made where these assumptions are met. Where there may be factors that undermine these assumptions, then an MR study should be considered genetic associations, not necessarily a cause-effect relationship.

When long-term randomised studies are not possible, Mendelian randomisation is a powerful tool to examine potential cause-effect relationships. But we should temper our enthusiasm for thinking anything genetic solves all methodological challenges in our field, as MR of nutritional exposures faces several methodological challenges itself that need to be considered.