Nevertheless, there are several caveats in interpreting the GSMR results. First, if the exposure is a composite trait that comprises multiple sub-phenotypes, we could not rule out the possibility that the effect of exposure on disease is driven by one of the sub-phenotypes. For instance, we have identified from the GSMR analysis that EduYears had effects on many diseases (Fig. 6). A conservative interpretation is that these are the effects of the genetic component of EduYears (e.g., cognitive ability and personality) on health outcomes. If we express EduYears = g + e, where g is the genetic component of EduYears and e is the residual component that includes environmental influence, then the SNPs identified from GWAS for EduYears are those associated with g rather than e, meaning that the GSMR analysis for EduYears was performed on g rather than e and thus did not provide any evidence whether e also has effects on diseases. Therefore, strictly speaking, the causative associations identified in this study are not definitive and need to be confirmed by follow-up randomized controlled trials (RCTs) in the
