The Mendelian Randomization Approach
Mendelian randomization is a method that allows one to test for, or in certain cases to estimate, a causal effect from observational data in the presence of confounding factors. It uses common genetic polymorphisms with well-understood effects on exposure patterns (e.g., propensity to drink alcohol) or effects that mimic those produced by modifiable exposures (e.g., raised blood cholesterol (Katan 1986)). Importantly, the genotype must only affect the disease status indirectly via its effect on the exposure of interest. Because genotypes are assigned randomly when passed from parents to offspring during meiosis, if we assume that choice of mate is not associated with genotype (panmixia), then the population genotype distribution should be unrelated to the confounders that typically plague observational epidemiology studies. In this regard, Mendelian randomization can be thought of as a “natural” RCT. From a statistical perspective, it is an application of the technique of instrumental variables (Thomas & Conti 2004, Didelez & Sheehan 2007), with genotype acting as an instrument for the exposure of interest.
Mendelian randomization relies on getting good estimates from genetic association studies. Misleading conclusions can also be drawn in the presence of linkage disequilibrium, genetic heterogeneity, pleiotropy, or population stratification (Davey Smith & Ebrahim 2003).
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