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Mendelian randomization

George Thanassoulis, MD, MSc
Christopher J O'Donnell, MD, MPH
Section Editor
Benjamin A Raby, MD, MPH
Deputy Editor
Jennifer S Tirnauer, MD


Mendelian randomization represents a novel epidemiologic study design that incorporates genetic information into traditional epidemiologic methods. Studies based on Mendelian randomization will likely become increasingly common as genetic knowledge of health and disease expands with data from genomewide association studies and genome sequencing. Mendelian randomization provides an approach to addressing questions of causality without many of the typical biases that impact the validity of traditional epidemiologic approaches.

While Mendelian randomization studies can provide important suggestive evidence for causal relations between risk factor and disease outcome, they are not true experiments and are dependent on several assumptions. Evidence from randomized controlled trials, when possible, should continue to guide clinical decisions. However, Mendelian randomization studies are increasingly being used to identify potential targets for new drugs prior to embarking on costly randomized controlled trials.

This topic will discuss the rationale and limitations of Mendelian randomization as a study design. The principles of Mendelian inheritance, which are the basis for randomization of this study design, are discussed separately. (See "Overview of Mendelian inheritance".)


The Mendelian randomization design was first proposed in 1986 to evaluate whether low levels of LDL cholesterol increase cancer risk [1]. Observational studies had reported a higher risk of cancer in individuals with low LDL levels, compared with subjects with normal or elevated LDL levels. However, biases implicit in observational studies could not be excluded as an explanation for the observed association.

Investigators proposed a natural experiment, suggesting that the effect of low LDL levels on cancer risk could be determined by comparing cancer rates in individuals with and without genotypes that predispose to low LDL level. The inheritance of a particular genotype, based on Mendel’s second law of independent assortment, was far less likely to be influenced by lifestyle or environmental issues than LDL levels themselves. This hypothetical study, finally performed more than 20 years later when genetic data became more readily available, found no increased risk among individuals with lifelong low LDL levels [2].


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Literature review current through: May 2017. | This topic last updated: Jun 09, 2017.
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