Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Bipolar Disord. 2023 Aug;25(5):410-421. doi: 10.1111/bdi.13295. Epub 2023 Jan 16.
Due to the phenotypic heterogeneity and etiological complexity of bipolar disorder (BD), many patients do not respond well to the current medications, and developing novel effective treatment is necessary. Whether any BD genome-wide association study (GWAS) risk genes were targets of existing drugs or novel drugs that can be repurposed in the clinical treatment of BD is a hot topic in the GWAS era of BD.
A list of 425 protein-coding BD risk genes was distilled through the BD GWAS, and 4479 protein-coding druggable targets were retrieved from the druggable genome. The overlapped genes/targets were subjected to further analyses in DrugBank, Pharos, and DGIdb datasets in terms of their FDA status, mechanism of action and primary indication, to identify their potential for repurposing.
We identified 58 BD GWAS risk genes grouped as the druggable targets, and several genes were given higher priority. These BD risk genes were targets of antipsychotics, antidepressants, antiepileptics, calcium channel antagonists, as well as anxiolytics and analgesics, either existing clinically-approved drugs for BD or the drugs than can be repurposed for treatment of BD in the future. Those genes were also likely relevant to BD pathophysiology, as many of them encode ion channel, ion transporter or neurotransmitter receptor, or the mice manipulating those genes are likely to mimic the phenotypes manifest in BD patients.
This study identifies several targets that may facilitate the discovery of novel treatments in BD, and implies the value of conducting GWAS into clinical translation.
由于双相情感障碍（BD）的表型异质性和病因复杂性，许多患者对当前的药物治疗反应不佳，因此有必要开发新的有效治疗方法。在 BD 的 GWAS 时代，一个热门话题是，任何 BD 全基因组关联研究（GWAS）风险基因是否是现有药物或可重新用于 BD 临床治疗的新型药物的靶点。
通过 BD GWAS 提取了 425 个编码 BD 风险的蛋白编码基因列表，并从可用药基因组中检索了 4479 个编码可用药的靶点。在 DrugBank、Pharos 和 DGIdb 数据集，根据这些基因/靶点的 FDA 状态、作用机制和主要适应证，对重叠基因/靶点进行进一步分析，以确定它们重新用于治疗的潜力。
我们确定了 58 个 BD GWAS 风险基因，这些基因被归类为可用药靶点，其中一些基因具有更高的优先级。这些 BD 风险基因是抗精神病药、抗抑郁药、抗癫痫药、钙通道拮抗剂、以及抗焦虑药和镇痛药的靶点，这些药物要么是现有的 BD 临床批准药物，要么是未来可重新用于治疗 BD 的药物。这些基因也可能与 BD 病理生理学相关，因为其中许多基因编码离子通道、离子转运体或神经递质受体，或操纵这些基因的小鼠可能模拟 BD 患者表现出的表型。
这项研究确定了几个可能有助于在 BD 中发现新治疗方法的靶点，并暗示了将 GWAS 进行临床转化的价值。
