Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia.
Revisiting Antipsychotic Drug Actions Through Gene Networks Associated With Schizophrenia.
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DOI：
10.1176/appi.ajp.2017.17040410
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发表时间：
2018-07-01
期刊：
影响因子：
--
通讯作者：
Chen CH
中科院分区：
文献类型：
--
作者：
Kauppi K;Rosenthal SB;Lo MT;Sanyal N;Jiang M;Abagyan R;McEvoy LK;Andreassen OA;Chen CH
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，并揭示新的药物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。然而，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并不是孤立地发挥作用，而是与其他基因结合发挥作用。因此，我们利用蛋白质-蛋白质相互作用网络（interactome）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）。我们的结果表明，精神分裂症风险基因显着定位于相互作用组中（p=0.0015），形成独特的疾病模块。该模块的核心基因富含参与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。有趣的是，抗精神病药物的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（如认知功能障碍和阴性症状）的新药或药物再利用机会的合适靶点。这种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，从而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。
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. However, the 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. Thus, we utilized protein-protein interaction networks (interactome) to map antipsychotic drug targets (n=88) to networks of schizophrenia risk genes (n=328). Our results showed that schizophrenia risk genes were significantly localized in the interactome (p=0.0015), 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. Intriguingly, 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 dysfunction and negative symptoms. This network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multi-target anti-schizophrenia drugs. This approach is transferable to other diseases.
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影响因子：
25
作者：
Breen G;Li Q;Roth BL;O'Donnell P;Didriksen M;Dolmetsch R;O'Reilly PF;Gaspar HA;Manji H;Huebel C;Kelsoe JR;Malhotra D;Bertolino A;Posthuma D;Sklar P;Kapur S;Sullivan PF;Collier DA;Edenberg HJ
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Edenberg HJ
影响因子：
4.3
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影响因子：
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Rich, Stephen S.
影响因子：
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作者：
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Cerovac N
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
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