Internal medicine

Biology

Gene

Genotype

Randomization

Randomized controlled trial

Mendelian randomization

Genetic variants

Genetics

Medicine

Nature Reviews Methods Primers

Mendelian randomization (MR) is a term that applies to the use of genetic variation to address causal questions about how modifiable exposures influence different outcomes. The principles of MR are based on Mendel’s laws of inheritance and instrumental variable estimation methods, which enable the inference of causal effects in the presence of unobserved confounding. In this Primer, we outline the principles of MR, the instrumental variable conditions underlying MR estimation and some of the methods used for estimation. We go on to discuss how the assumptions underlying an MR study can be assessed and describe methods of estimation that are robust to certain violations of these assumptions. We give examples of a range of studies in which MR has been applied, the limitations of current methods of analysis and the outlook for MR in the future. The differences between the assumptions required for MR analysis and other forms of epidemiological studies means that MR can be used as part of a triangulation across multiple sources of evidence for causal inference. Mendelian randomization is a technique for using genetic variation to examine the causal effect of a modifiable exposure on an outcome such as disease status. This Primer by Sanderson et al. explains the concepts of and the conditions required for Mendelian randomization analysis, describes key examples of its application and looks towards applying the technique to growing genomic datasets.