Insight into rheumatological cause and effect through the use of Mendelian randomization

Mendelian randomization analysis makes use of random inheritance of genetic variants to limit confounding in tests for causal relationships between risk factors and disease outcomes. This Review considers the current and future applications, as well as the limitations, of Mendelian randomization in rheumatology. Establishing causality of risk factors is important to determine the pathogenetic mechanisms underlying rheumatic diseases, and can facilitate the design of interventions to improve care for affected patients. The presence of unmeasured confounders, as well as reverse causation, is a challenge to the assignment of causality in observational studies. Alleles for genetic variants are randomly inherited at meiosis. Mendelian randomization analysis uses these genetic variants to test whether a particular risk factor is causal for a disease outcome. In this Review of the Mendelian randomization technique, we discuss published results and potential applications in rheumatology, as well as the general clinical utility and limitations of the approach.