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JAMA Guide to Statistics and Methods
November 21, 2017

Mendelian Randomization

Author Affiliations
  • 1Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston
  • 2Cardiovascular Disease Initiative, Broad Institute, Cambridge, Massachusetts
JAMA. 2017;318(19):1925-1926. doi:10.1001/jama.2017.17219

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.

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