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.

The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328).

Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH, and HCN families were not connected to existing antipsychotics but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia, such as cognitive or negative symptoms.

The network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multitarget antischizophrenia drugs. This approach is transferable to other diseases.

抗精神病药物是在 20 世纪 50 年代偶然发现的，但其作用机制仍不清楚。更好地了解精神分裂症发病机制可以揭示当前药物的作用，并揭示新的“可成药”途径来满足未满足的治疗需求。最近的全基因组关联研究为描述疾病基因网络和揭示药物与疾病的关系提供了前所未有的机会。精神分裂症风险基因和抗精神病药物靶点之间的多基因重叠已被证明，但构成这种重叠的具体基因和途径尚未确定。多基因疾病的风险基因不是孤立运作的，而是通过基因产物之间的蛋白质-蛋白质相互作用与其他基因结合。

蛋白质相互作用组用于将抗精神病药物靶点 (N=88) 映射到精神分裂症风险基因网络 (N=328)。

精神分裂症风险基因显着定位于相互作用组中，形成独特的疾病模块。该模块的核心基因富含涉及发育生物学和认知的基因，这可能在精神分裂症病因学中发挥核心作用。抗精神病药物靶点与核心疾病模块重叠，并包含多巴胺以外的多种途径。一些重要的风险基因，如CHRN 、 PCDH和HCN家族，与现有的抗精神病药物无关，但可能是治疗精神分裂症其他方面（例如认知或阴性症状）的新药或药物再利用机会的合适靶点。

网络医学方法提供了一个平台来整理疾病遗传学和药物基因相互作用的信息，以将重点从抗精神病药物的开发转移到多靶点抗精神分裂症药物。这种方法可以应用于其他疾病。