The basic premise of Mendelian randomization relies on genetic variants that explain variation in the exposure, but do not affect the disease outcome except possibly through the exposure. Such genetic variants are known as instrumental variables (IVs) (Greenland, 2000). Subgroups of individuals with differing numbers of alleles of a genetic IV can be thought of as having been randomized to receive a different mean level of the exposure during their life course (Davey Smith and Ebrahim, 2005; Nitsch et al., 2006). If the randomization is indeed uncontaminated (in the sense that a person's genetic subgroup is independent of all factors, except the exposure and any causal consequence of the exposure), then differences in the outcome between genetic subgroups can be causally attributed to the exposure (Didelez and Sheehan, 2007). The following three assumptions are necessary for a genetic variant to be a valid IV (Martens et al., 2006): IV1: the variant is predictive of the exposure;IV2: the variant is independent of any confounding factors of the exposure—outcome association;IV3: the variant is conditionally independent of the outcome given the exposure and the confounding factors.
