The use of Mendelian randomisation to identify causal cancer risk factors: promise and limitations

The use of observational analyses, such as classical epidemiological studies or randomised controlled trials (RCTs), to infer causality in cancer may be problematic due to both ethical reasons and technical issues, such as confounding variables and reverse causation. Mendelian randomisation (MR) is an epidemiological technique that uses genetic variants as proxies for exposures in an attempt to determine whether there is a causal link between an exposure and an outcome. Given that genetic variants are randomly assigned during meiosis according to Mendel's first and second laws of heritability, MR may be thought of as a 'natural' RCT and is therefore less vulnerable to the aforementioned problems. MR has the potential to help identify new, and validate or disprove previously implicated, modifiable risk factors in cancer, but it is not without limitations. This review provides a brief description of the history and principles of MR, as well as a guide to basic MR methodology. The bulk of the review then examines various limitations of MR in more detail, discussing some of the proposed solutions to these problems. The review ends with a brief section detailing the practical implementation of MR, with examples of its use in the study of cancer, and an assessment of its utility in identifying cancer predisposition traits. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.