Synonyms: Interaction MR
Studies that assess interaction between (typically) one genetic variant and a non-genetic factor with respect to a given outcome. These can be useful in several MR contexts. For example, some genetic variants for smoking, alcohol and other factors on a metabolite or mechanism that is caused by the exposure but does not directly affect levels of the exposure. In these circumstances, if the exposure causes the outcome of interest, the genetic variant would only be expected to associate with the outcome in those who have ever smoked/drunk alcohol or been exposed to the exposure. In those who have never been exposed, an association between the gene and the outcome would not be expected. Thus, a G×E study, where E is defined as ever versus never exposed, would provide MR evidence for a causal effect.
Sometimes, G×E can be used to investigate mechanisms. For example, if the genetic variant blocks the postulated mediating mechanism from the exposure to the outcome, then the exposure would not be expected to be associated with the outcome among carriers of the mediator-blocking genotype. G×E can be exploited to mitigate bias due to horizontal pleiotropy in MR. Adequate statistical power typically requires very large samples. Many published studies did not properly adjust for potential confounders.
References
- Keller MC. Gene x environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution. Biol Psychiatry 2014; 75: 18-24.
- Davey Smith G. Use of genetic markers and gene-diet interactions for interrogating population-level causal influences of diet on health. Genes and Nutrition 2011; 6: 27-43.