Commentary: Mendelian randomization and gene-environment interaction

Abstract

The above examples illustrate the potential for studies of Mendelian randomization to ask challenging questions regarding the role of environmental, lifestyle, and endogenous factors in the development of chronic disease that are beyond the limit of traditional epidemiological studies, although they also indicate some potential pitfalls. One could think of other possible carcinogens where such an approach would be useful. For example, both specific pesticides and sunlight exposure have both been linked to the development of non-Hodgkin's lymphoma, although any traditional study of either of these exposures is prone to both bias and confounding. Identification of genes that are responsible for metabolizing potential pesticide carcinogens, or modulating any immune suppression effect from sunlight, would prove instrumental in identifying the causal nature of these exposures. Similarly, potential risk factors for breast cancer that remain to be clarified include dietary fat, passive smoking and specific endogenous hormones. Again, identification of functional genes that resulted in significant between-person variation for these potential carcinogens would enable the testing of specific causal hypotheses. However, we are still very much in ignorance regarding the role of specific genes in metabolizing most of the above exposures and it is likely that the biggest drawback to the conduct of useful Mendelian randomization studies will be the limited amount of information available on genetic metabolism of potential risk factors. Further identification of metabolizing genes, including estimation of between-person variation should clearly become an area of higher priority. Regarding other potential problems, pleiotropy, or the multiple function of individual genes, only becomes a problem if another compound being metabolized by a gene also affects the risk for the disease under question, and the two compounds are associated, resulting in confounding. If this function is known then it may be possible to adjust for the effect of the secondary compound. Possibilities for such confounding are however likely to be much more limited than those encountered with lifestyle or environmental exposures. Confounding may also occur if the gene influences the potential for exposure, such as that with ADHIB and alcohol consumption. Such situations are likely to be restricted to individuals with an increased genetic tendency to experience a toxic reaction against a particular substance, or to addictive tendencies that are at least partially genetically regulated, e.g. by nicotine and dopamine receptor genes. Similarly, genetic confounding may occur via linkage disequilibrium with other causal genes in the close vicinity of the gene under study. Again, the potential for this is likely to be limited. The final limitation of Mendelian randomization studies is one shared by traditional randomized controlled trials, i.e. the lack of replicability of studies due to their small sample size. While Mendelian randomization studies will clearly allow for a focussed testing of specific hypotheses, it will be important not to forget the lessons of the first generation of genetic association studies: that results based on small sample sizes are more likely to confuse than enlighten. © International Epidemiological Association 2004; all rights reserved.