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This JAMA Guide to Statistics and Methods reviews the concepts underlying mendelian randomization and provides examples of its application to clinical trial design.

Mendelian randomization uses genetic variants to determine whether an observational association between a risk factor and an outcome is consistent with a causal effect.1 Mendelian randomization relies on the natural, random assortment of genetic variants during meiosis yielding a random distribution of genetic variants in a population.1 Individuals are naturally assigned at birth to inherit a genetic variant that affects a risk factor (eg, a gene variant that raises low-density lipoprotein [LDL] cholesterol levels) or not inherit such a variant. Individuals who carry the variant and those who do not are then followed up for the development of an outcome of interest. Because these genetic variants are typically unassociated with confounders, differences in the outcome between those who carry the variant and those who do not can be attributed to the difference in the risk factor. For example, a genetic variant associated with higher LDL cholesterol levels that also is associated with a higher risk of coronary heart disease would provide supportive evidence for a causal effect of LDL cholesterol on coronary heart disease.

One way to explain the principles of mendelian randomization is through an example: the study of the relationship of high-density lipoprotein (HDL) cholesterol and triglycerides with coronary heart disease. Increased HDL cholesterol levels are associated with a lower risk of coronary heart disease, an association that remains significant even after multivariable adjustment.2 By contrast, an association between increased triglyceride levels and coronary risk is no longer significant following multivariable analyses. These observations have been interpreted as HDL cholesterol being a causal driver of coronary heart disease, whereas triglyceride level is a correlated bystander.2 To better understand these relationships, researchers have used mendelian randomization to test whether the observational associations between HDL cholesterol or triglyceride levels and coronary heart disease risk are consistent with causal relationships.3-5


Why Is Mendelian Randomization Used?

Basic principles of mendelian randomization can be understood through comparison with a randomized clinical trial. To answer the question of whether raising HDL cholesterol levels with a treatment will reduce the risk of coronary heart disease, individuals might be randomized to receive a treatment that raises HDL cholesterol levels and a placebo that does not have this effect. If there is a causal effect of HDL cholesterol on coronary heart disease, a drug that raises HDL cholesterol levels should eventually reduce the risk of coronary heart disease. However, randomized trials are costly, take a great deal of time, and may be impractical to carry out, or there may not be an intervention to test a certain hypothesis, limiting the number of clinical questions that can be answered by randomized trials.

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