The relationship between phenocopy and genocopy (see Box 2) lies at the heart of the Mendelian randomization approach, which seeks to leverage genetic information to identify causal relationships between modifiable exposures and disease outcomes. The principles of Mendelian randomization have been described in detail elsewhere [6–8]. In brief, genetic variants are used as proxies (i.e., instrumental variables) for modifiable exposures. If the assumptions of Mendelian randomization hold, these proxies should not be associated with the factors that confound observational associations and will not be subject to reverse causation. This has become an increasingly popular technique for establishing whether an observational association between an exposure and an outcome is likely to be causal. However, while Mendelian randomization makes use of information obtained (principally) via GWAS, our argument is that the same reasoning can directly inform our interpretation of GWAS results.
