What is Mendelian randomisation?

If epidemiologists are compared with fishermen, causality is the big fish. It is elusive to find, difficult to catch, and claims to have measured it are often exaggerated. But, despite the challenge, demonstration of causal relations remains a central aim of epidemiological inquiry. Mendelian randomisation is becoming a commonly used technique to make assessment of causality possible from observational data.1 For example, in coronary disease it has recently strengthened the case for a causal role of lipoprotein(a)2 and weakened the case of C reactive protein.3

To perform Mendelian randomisation, we look for a genetic variant with three key features. Firstly, it is associated with the risk factor of interest. Secondly, it divides the observed population into groups similar to arms in a randomised trial, which do not systematically differ with respect to any confounding variable.4 This ensures that any difference in the outcome is because of the genetic variant. Thirdly, it affects the outcome only through the risk factor of interest and not by other biological pathways. Provided these key features hold, we can infer a causal association of the risk factor on the …