Can the GWA data be used to re-evaluate major pathophysiological hypotheses of schizophrenia such as the dopamine hypothesis? Data obtained from GWA studies offer great opportunities for addressing such key questions. Firstly, to test a certain pathophysiological hypothesis, the relevant data can be extracted (e.g. SNP data from genes involved in dopaminergic neurotransmission) and specifically tested for association with the diagnosis of schizophrenia. The number of statistical tests can be greatly reduced in comparison to genome-wide analyses, reducing the necessary correction factor applied for multiple testing, and this approach thus enables the identification of smaller genetic effects. Secondly, it is possible that dopaminergic dysfunction may emerge as a downstream consequence of genetic variation in the (non-canonical) candidate genes identified in GWA studies, thereby reconciling the seemingly inconsistent findings that genetic associations with dopaminergic pathway genes are rather weak, whereas “higher level” (e.g. neuroimaging) findings linking dopamine to psychosis are robust.
