Mendelian randomization as applied to coronary heart disease, including recent advances incorporating new technology.

What is Mendelian Randomization? The field of epidemiology has struggled to make headway in determining whether exposures are causal factors for complex diseases, largely because of the problems of confounding, reverse causation, and bias. To overcome the problems inherent in observational studies, epidemiologists have proposed using genetic variants as proxies for exposures.1,2 The idea is to exploit genetic variants that influence exposure propensity or are involved in metabolism, transport, or cellular uptake of the exposure or are otherwise associated with exposure levels. The advantage of using genetic variants is that because of the random assignment of alleles with respect to subsequent lifestyle factors, they are considered independent of factors that may confound epidemiological studies (see limitations of Mendelian randomization in the next section). Thus, Mendelian randomization combines the 2 fields of epidemiology and genetics, but rather than aiming to understand genetic mechanisms leading to disease, the principle is to use a genetic variant as a proxy for an environmental exposure or intermediate phenotype that may be on the causal pathway of the disease in question. This method is not without problems; however, advances in genetics are helping to overcome these limitations and are likely to increase its utility in uncovering risk factors for disease.