Mendelian Randomisation: Concepts, Opportunities, Challenges, and Future Directions

Abstract

Mendelian randomisation is an approach in genetic epidemiology that uses genetic variants as instrumental variables to investigate the causal relationship between genetically proxied exposures and health outcomes. During the last years, the number of published Mendelian randomisation studies increased tremendously. There are several opportunities of Mendelian randomisation including obtaining potential causal relationships between both exogenous and endogenous exposures and outcomes and for identifying and prioritising drug-targets to inform clinical trials. However, it is also important to be aware of its challenges. This includes the reliability of results under the assumptions on instrumental variables, being aware of potential biases, the correct and critical interpretation of findings and comparison to the results of randomised controlled trials, as well as the availability of genetic data on specific subgroups. This review provides a comprehensive overview of the opportunities and challenges of Mendelian randomisation and presents key future perspectives.

Keywords: Mendelian randomisation; challenges; omics; opportunities; perspective; sex-specific; subgroups.

Figure 1

Number of publications on Mendelian randomisation studies until 2024. The data depicted in this figure have been extracted from PubMed on February 24^th 2025 using the search terms “Mendelian randomization” OR “Mendelian randomisation”. Publications from 2025 have been excluded.

Figure 2

Directed acyclic graphs on selection bias in Mendelian randomisation analyses. Directed acyclic graphs where G represents the instrumental variable, X the exposure, U the confounder, Y the outcome and where selection (S) leads to selection bias if it is dependent on levels of the exposure (panel A) or outcome (panel B).