Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia
Gene-set analysis based on the pharmacological profiles of drugs to identify repurposing opportunities in schizophrenia
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DOI：
10.1177/0269881116653109
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发表时间：
2016-08-01
影响因子：
4.1
通讯作者：
Breen, Gerome
中科院分区：
文献类型：
--
作者：
de Jong, Simone;Vidler, Lewis R.;Breen, Gerome
全基因组关联研究已经确定了数千种与复杂遗传疾病有关的新的遗传关联，从而为新药开发确定了潜在的药理靶点。在精神分裂症中，已经确定了108个符合全基因组意义的保守定义的基因座，并发现了数百个额外的亚阈值关联，其中蕴含着关于精神分裂症遗传病因学的信息。在本研究中，我们使用基于已知的化合物结合靶点的基因集分析来确定与精神分裂症相关基因关联最强的药物通路，目的是为新的治疗范例，特别是在多靶点药物开发中，识别潜在的药物重新定位机会和线索。我们汇编了9389个基因集(2496个具有独特基因含量的基因)，并从PGC2-SCZ分析中询问了基于基因的p值。虽然没有一种药物超过试验的广泛意义(更正p
Genome-wide association studies (GWAS) have identified thousands of novel genetic associations for complex genetic disorders, leading to the identification of potential pharmacological targets for novel drug development. In schizophrenia, 108 conservatively defined loci that meet genome-wide significance have been identified and hundreds of additional sub-threshold associations harbour information on the genetic aetiology of the disorder. In the present study, we used gene-set analysis based on the known binding targets of chemical compounds to identify the drug pathways' most strongly associated with schizophrenia-associated genes, with the aim of identifying potential drug repositioning opportunities and clues for novel treatment paradigms, especially in multi-target drug development. We compiled 9389 gene sets (2496 with unique gene content) and interrogated gene-based p-values from the PGC2-SCZ analysis. Although no single drug exceeded experiment wide significance (corrected p