Mendelian randomization: Using genes as instruments for making causal inferences in epidemiology

TLDR

Observational epidemiology is limited by confounding and reverse causation, and while instrumental variable methods have been used in other sciences, Mendelian randomization—using germline variants as proxies for exposures—offers a trial‑like approach to strengthen causal inference. The paper outlines Mendelian randomization, compares it to IV methods, illustrates its implementation, and discusses its limitations and mitigation strategies. Mendelian randomization employs germline genetic variants as instruments for modifiable exposures, enabling IV analysis within observational studies, and the authors provide concrete examples of its application. High‑profile trials have shown that interventions identified by observational studies can yield markedly different results when tested in randomized controlled trials.

Abstract

Observational epidemiological studies suffer from many potential biases, from confounding and from reverse causation, and this limits their ability to robustly identify causal associations. Several high-profile situations exist in which randomized controlled trials of precisely the same intervention that has been examined in observational studies have produced markedly different findings. In other observational sciences, the use of instrumental variable (IV) approaches has been one approach to strengthening causal inferences in non-experimental situations. The use of germline genetic variants that proxy for environmentally modifiable exposures as instruments for these exposures is one form of IV analysis that can be implemented within observational epidemiological studies. The method has been referred to as 'Mendelian randomization', and can be considered as analogous to randomized controlled trials. This paper outlines Mendelian randomization, draws parallels with IV methods, provides examples of implementation of the approach and discusses limitations of the approach and some methods for dealing with these.