Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder
Using genetic drug-target networks to develop new drug hypotheses for major depressive disorder
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DOI：
10.1038/s41398-019-0451-4
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发表时间：
2019-03-15
影响因子：
6.8
通讯作者：
Breen, Gerome
中科院分区：
文献类型：
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作者：
Gaspar, Helena A.;Gerring, Zachary;Breen, Gerome
精神病学基因组学联盟（PGC）的重度抑郁症（MDD）工作组发表了一项针对130,664例重度抑郁症的全基因组关联研究（GWAS），确定了44种风险变异。我们利用这些结果来研究潜在的药物靶点和重新利用的机会。使用在线工具Drug Targetor (drugtargetor.com)，我们构建了易于解释的双部分药物-靶点网络，整合了药物与其靶点之间的相互作用、全基因组关联统计以及不同组织中基因预测的表达水平。我们还调查了可能影响重度抑郁症的药物-靶标关系。MAGMA用于进行通路分析，S-PrediXcan用于研究患者与对照组的组织特异性表达水平的方向性。在主要组织相容性复合体（MHC）区域之外，153个蛋白质编码基因经多次检测校正后与MAGMA的MDD显著相关；在这些基因中，预计有5个在大脑区域下调或上调，24个是已知的可药物基因。几类药物显著富集，包括单胺再摄取抑制剂、性激素、抗精神病药和抗组胺药，表明对重度抑郁症的影响和潜在的重新利用机会。这些发现不仅需要在模型系统和临床检查中得到验证，而且还表明GWAS可能成为重度抑郁症和其他精神疾病的新治疗假设的丰富来源，这些疾病需要新的和更好的治疗选择。
The major depressive disorder (MDD) working group of the Psychiatric Genomics Consortium (PGC) has published a genome-wide association study (GWAS) for MDD in 130,664 cases, identifying 44 risk variants. We used these results to investigate potential drug targets and repurposing opportunities. We built easily interpretable bipartite drug-target networks integrating interactions between drugs and their targets, genome-wide association statistics, and genetically predicted expression levels in different tissues, using the online tool Drug Targetor (drugtargetor.com). We also investigated drug-target relationships that could be impacting MDD. MAGMA was used to perform pathway analyses and S-PrediXcan to investigate the directionality of tissue-specific expression levels in patients vs. controls. Outside the major histocompatibility complex (MHC) region, 153 protein-coding genes are significantly associated with MDD in MAGMA after multiple testing correction; among these, five are predicted to be down or upregulated in brain regions and 24 are known druggable genes. Several drug classes were significantly enriched, including monoamine reuptake inhibitors, sex hormones, antipsychotics, and antihistamines, indicating an effect on MDD and potential repurposing opportunities. These findings not only require validation in model systems and clinical examination, but also show that GWAS may become a rich source of new therapeutic hypotheses for MDD and other psychiatric disorders that need new-and better-treatment options.