Mendelian randomisation: A powerful and inexpensive method for identifying and excluding non-genetic risk factors for colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in economically developed countries and a major cause of cancer-related mortality. The importance of lifestyle and diet as major determinants of CRC risk is suggested by differences in CRC incidence between countries and in migration studies. Previous observational epidemiological studies have identified associations between modifiable environmental risk factors and CRC, but these studies can be susceptible to reverse causation and confounding, and their results can therefore conflict. Mendelian randomisation (MR) analysis represents an approach complementary to conventional observational studies examining associations between exposures and disease. The MR strategy employs allelic variants as instrumental variables (IVs), which act as proxies for non-genetic exposures. These allelic variants are randomly assigned during meiosis and can therefore inform on life-long exposure, whilst not being subject to reverse causation. In previous studies MR frameworks have associated several modifiable factors with CRC risk, including adiposity, hyperlipidaemia, fatty acid profile and alcohol consumption. In this review we detail the use of MR to investigate and discover CRC risk factors, and its future applications.