It is important to emphasise that the implication of schizophrenia risk alleles predicting cannabis use, if true, does not rule out the possibility of cannabis independently being a risk factor for schizophrenia. A bi-directional association between cannabis use and psychosis has previously been suggested40. Further, one caveat to interpreting the direction of causation concerns the discovery sample used to identify schizophrenia risk alleles. The schizophrenia GWAS sample will likely include many more cannabis users among cases than controls. This may lead to an excess of causal SNPs associated with cannabis use, as opposed to schizophrenia itself, identified as schizophrenia risk alleles. Only if the discovery schizophrenia sample was comprised entirely of non-cannabis users could causation be inferred without any risk of confounding. This is an important consideration as to whether polygenic risk scores over-estimate individuals’ un-modifiable genetic risk by including their genetic predisposition to modifiable environmental risk factors.
