Spatial and functional profiles distinguish target sets of Parkinson’s disease and antipsychotic drugs with different clinical effects

Several studies have examined the genetic factors shared between Parkinson's disease (PD) and schizophrenia (SZ), but the biological themes underlying their clinical relationships remain less explored. We employed systematic transcriptomic and network analyses to examine the genes targeted by two sets of antipsychotic drugs (APDs) - first-generation APDs inducing Parkinsonism and second-generation APDs typically effective against psychotic symptoms in PD - and two sets of PD drugs, one at risk of psychosis and the other with a lower risk of psychosis. Although global brain expression patterns did not effectively differentiate between the targets of the two sets of APDs, they did differentiate the targets of the two PD drug sets. However, both APD and PD target sets showed differences in mean expression levels in specific brain regions. Moreover, they showed significant enrichment for genes highly expressed in distinct adult and prenatal brain structures relative to the overall distribution of such genes among all brain-expressed genes. Specific neurotransmitter systems, either individually or in combinations, appeared to underlie the clinically informed drug categories, indicating their differential roles in inducing or not inducing PD and psychosis. Additionally, the target sets formed distinct network modules representing different biological mechanisms and exhibited differential proximity to putative PD and SZ risk genes in the human interactome. In summary, our study identified specific spatial and functional features that distinguish the target sets of PD and antipsychotic drugs with different clinical effects.