Basic MR analysis: Testing for a causal effect.

The first step in any MR approach involves finding genetic polymorphisms to use as proxies, or “instruments,” for a target exposure.  Testing for an association between  a genetic instruments and the  outcome of interest is a valid test of the hypothesis that the exposure causally affects the outcome (9, 11).  This requires that all genetic variants satisfy the instrumental variable assumptions (IV1-IV3):

 

  • IV1: A genetic variant is associated with the exposure

  • IV2: A genetic variant is notassociated with any confounders of the exposure and outcome

  • IV3: The genetic variant notassociated of the outcome conditional on the exposure and all confounders

The IV assumptions are represented by the causal diagram in Figure 1.


Figure 1: Hypothesised relationship between genetic variant Gk, modifiable exposure X and outcome Y in the presence of unobserved confounder U. Dashed lines represent violations of the instrumental variable assumptions.

The causal effect of a unit-change in X on Y is represented by the parameter . If a gene is a valid IV then it should not be associated with Y if = 0.  If the two are associated, this points to a non-zero causal effect, but extended methods are required to estimate it.

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