IDENTIFYING DRUG TARGETS FOR SCHIZOPHRENIA THROUGH GENE PRIORITIZATION

IF 6.1 2区 医学 Q1 CLINICAL NEUROLOGY
Karl Heilbron , Julia Kraft , Alice Braun , Swapnil Awasthi , Georgia Panagiotaropoulou , Marijn Schipper , Nathaniel Bell , Danielle Posthuma , Antonio Pardiñas , Stephan Ripke
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Abstract

The latest schizophrenia GWAS meta-analysis found 287 loci that reached genome-wide statistical significance (67,390 cases and 94,015 controls). In these loci, 120 genes were prioritized using fine-mapping, summary-based Mendelian Randomization (SMR), and enhancer-promoter interaction (via Hi-C). However, these methods only use information within a given locus, ignoring information from the rest of the genome. Combining locus-based approaches with tools that incorporate genome-wide information such as the Polygenic Priority Score (PoPS) have been shown to improve gene prioritization precision. To more accurately characterize genes that play a role in schizophrenia etiology, we prioritized 62 genes based on their distance to GWAS signals, PoPS, fine-mapped coding variants, and ultra-rare coding variant burden tests. We prioritized DRD2, the target of most approved antipsychotics, which was not highlighted by previous efforts. In addition, we prioritized 9 genes that are targeted by approved or investigational drugs and may therefore present drug repurposing opportunities. These included drugs targeting calcium channels (CACNA1C and CACNB2), glutamatergic receptors (GRIN2A and GRM3), and GABAB receptor (GABBR2). We highlighted 3 additional genes (PDE4B, VRK2, and PLCL2) in loci that are shared with a recent addiction GWAS. While it is challenging to assess psychotic symptoms in rodents, high-quality rodent addiction models exist for a wide range of substances. Modulation of these genes could be tested in rodent addiction models and, if successful, may warrant further testing in human clinical trials of addiction and/or schizophrenia. Adding to previous gene prioritization efforts, we hope that our list of prioritized genes will ultimately facilitate the development of new medicines for people living with schizophrenia.
通过基因优先排序确定精神分裂症的药物靶点
最新的精神分裂症全球基因组研究荟萃分析发现,有 287 个基因位点达到了全基因组统计学意义(67390 例病例和 94015 例对照)。在这些基因座中,有 120 个基因通过精细作图法、基于孟德尔随机化的总结法(SMR)和增强子-启动子相互作用法(通过 Hi-C)进行了优先排序。然而,这些方法只使用了特定基因座内的信息,忽略了基因组其他部分的信息。事实证明,将基于基因座的方法与包含全基因组信息的工具(如多基因优先级评分(PoPS))相结合,可以提高基因优先级排序的精确度。为了更准确地描述在精神分裂症病因学中发挥作用的基因,我们根据基因与 GWAS 信号的距离、PoPS、精细映射编码变异以及超罕见编码变异负担测试,对 62 个基因进行了优先排序。我们优先选择了 DRD2,它是大多数已批准的抗精神病药物的靶点,而之前的研究并未突出这一靶点。此外,我们还优先选择了 9 个基因,这些基因是已批准药物或在研药物的靶点,因此可能会带来药物再利用的机会。这些基因包括靶向钙通道(CACNA1C 和 CACNB2)、谷氨酸能受体(GRIN2A 和 GRM3)和 GABAB 受体(GABBR2)的药物。我们还强调了另外 3 个基因(PDE4B、VRK2 和 PLCL2),它们的基因位点与最近的一项成瘾 GWAS 研究共享。虽然在啮齿类动物中评估精神病症状具有挑战性,但对于各种物质都存在高质量的啮齿类动物成瘾模型。可以在啮齿类动物成瘾模型中测试对这些基因的调节,如果成功,可能需要在成瘾和/或精神分裂症的人类临床试验中进一步测试。在以往基因优先排序工作的基础上,我们希望我们的优先排序基因列表最终能促进精神分裂症患者新药的开发。
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来源期刊
European Neuropsychopharmacology
European Neuropsychopharmacology 医学-精神病学
CiteScore
10.30
自引率
5.40%
发文量
730
审稿时长
41 days
期刊介绍: European Neuropsychopharmacology is the official publication of the European College of Neuropsychopharmacology (ECNP). In accordance with the mission of the College, the journal focuses on clinical and basic science contributions that advance our understanding of brain function and human behaviour and enable translation into improved treatments and enhanced public health impact in psychiatry. Recent years have been characterized by exciting advances in basic knowledge and available experimental techniques in neuroscience and genomics. However, clinical translation of these findings has not been as rapid. The journal aims to narrow this gap by promoting findings that are expected to have a major impact on both our understanding of the biological bases of mental disorders and the development and improvement of treatments, ideally paving the way for prevention and recovery.
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