Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia

Objective:Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel “druggable” pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated, but specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation but in combination with other genes through protein-protein interactions among gene product.Method:The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328).Results:Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease mod...