Leveraging genetic and electronic health record data to identify novel targets and drugs for treating alcohol use disorder

项目摘要/摘要 美国食品和药物管理局批准了四种治疗酒精使用障碍(AUD)的药物 (FDA)，许多患者并没有从中受益。此外，尽管全基因组关联研究(GWAS) 酒精消费和有问题的酒精使用(PAU；即结合AUD诊断和 有害饮酒的测量)产生了许多显著的单核苷酸多态(SNPs)，这些SNPs影响 风险方面，这些药物几乎没有产生治疗AUD的药物靶点。因此，确定药物靶标的需求尚未得到满足。 用于开发治疗AUD的新型和/或再利用药物。最近的研究表明，靶向 有遗传支持的疾病机制可以提高药物开发的成功率， (即围绕疾病相关基因的生物网络)丰富了已批准药物的靶标。 因此，影响饮酒和PAU风险的基因及其相关模块可能会产生新的靶点 以及用于治疗性再利用的药物。此外，大型电子健康记录(EHR)的可用性 数据集使人们有可能探索接触FDA批准的药物是否会导致 与批准的医疗条件不同的医疗条件，如澳元，并有可能被重新调整用途。 这项建议将建立在研究小组先前工作的基础上，并利用基因组学方面的进展和获得 退伍军人事务部(VA)EHR通过退伍军人信息学和计算基础设施(Vinci)：1)阐明 与酒精消费和PAU有关的单元(目标1和3)；和2)确定有希望再利用的药物 治疗AUD(目标2)。AIMS 1-2的一般假设是：1)所识别的模块中涉及的基因 将成为众多已批准药物的靶标；以及2)在退伍军人事务部电子病历中有足够患者数据的药物， 在倾向得分分析中，将有证据表明它们减少了酒精消费。假设 目标3是分析将确定为生物过程而丰富的排名靠前的模块 与酒精消费和PAU的相关性。总而言之，这项建议结合了精神遗传学和 药物流行病学方法识别新靶点和评价有望改变用途的药物 治疗澳元。一种理论上的、遗传数据驱动的方法来选择有前景的FDA批准的药物和 然后在EHR中使用倾向评分方法进行测试，这在精神病学中是以前没有做过的， 包括澳元。这个项目是由于在酒精消费和PAU方面的最新进展而成为可能的， 药物靶标连接，以及培养用于遗传和其他分析的EHR。这种药物优先排序的方法 能否发现可在后续临床试验中测试的独特药物和可在临床前评估的新靶点 学习。

PROJECT SUMMARY/ABSTRACT While four medications for treating alcohol use disorder (AUD) are approved by the Food and Drug Administration (FDA), many patients do not benefit from them. Moreover, while genome-wide association studies (GWASs) of alcohol consumption and problematic alcohol use (PAU; i.e., a phenotype that combines AUD diagnoses and a measure of harmful drinking) have yielded many significant single nucleotide polymorphisms (SNPs) that affect risk, these have yielded few drug targets for treating AUD. Hence, there is an unmet need to identify drug targets for the development of novel and/or repurposed drugs to treat AUD. Recent research indicates that targeting disease mechanisms with genetic support can increase the success rate in drug development and that modules (i.e., biological networks surrounding disease-associated genes) are enriched for targets of approved drugs. Thus, genes affecting alcohol consumption and risk of PAU and their associated modules could yield new targets and drugs for therapeutic repurposing. Furthermore, the availability of large electronic health records (EHR) datasets makes it possible to explore whether exposure to FDA-approved drugs can lead to improvements in medical conditions other than the ones for which they are approved, such as AUD, and potentially be repurposed. This proposal will build upon prior work by the study team and leverage advances in genomics and access to the Veterans Affairs (VA) EHR through the VA Informatics and Computing Infrastructure (VINCI) to: 1) elucidate modules linked to alcohol consumption and PAU (Aims 1 and 3); and 2) identify promising drugs for repurposing to treat AUD (Aim 2). The general hypotheses for Aims 1-2 are: 1) the genes implicated in the identified modules will be targeted by numerous approved drugs; and 2) of the drugs with sufficient patient data in the VA EHR, there will be evidence that they reduce alcohol consumption in propensity score analyses. The hypothesis for Aim 3 is that the analysis will identify top ranked modules that are enriched for biological processes with relevance to alcohol consumption and PAU. In sum, this proposal combines psychiatric genetic and pharmacoepidemiologic methods to identify novel targets and evaluate promising drugs to be repurposed for treating AUD. An atheoretical, genetic data-driven approach to selecting promising FDA-approved drugs and then testing them in the EHR using propensity score methods has not previously been done in psychiatry, including for AUD. This project is made possible by recent advances in GWAS of alcohol consumption and PAU, drug target linking, and the cultivation of EHRs for genetic and other analyses. This approach to drug prioritization could uncover unique drugs to be tested in follow-up clinical trials and novel targets to be evaluated in preclinical studies.