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

利用遗传和电子健康记录数据来确定治疗酒精使用障碍的新靶点和药物

• 批准号: 10629294
• 负责人: Joshua Charles Gray
• 金额: $ 54.6万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629294
• 关键词: Adult; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Algorithms; Biological; Biological Process; Caring; Catalogs; Chromatin; Chronic Disease; Clinical Trials; Data; Data Set; Development; Diagnosis; Disease; Drug Exposure; Drug Interactions; Drug Targeting; Electronic Health Record; Evaluation; Exposure to; Future; Gene Structure; Genes; Genetic; Genome; Genomics; Goals; Health; Impairment; Informatics; Infrastructure; Integrated Health Care Systems; Link; Measures; Medical; Methods; Molecular Conformation; Occupational; Occupations; Ontology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacoepidemiology; Phenotype; Proteins; Psychiatry; Quantitative Trait Loci; Reporting; Research; Review Literature; Risk; Scoring Method; Single Nucleotide Polymorphism; Testing; Therapeutic; United States Department of Veterans Affairs; United States Food and Drug Administration; Untranslated RNA; alcohol risk; alcohol use disorder; causal variant; cohort; drinking; drug candidate; drug development; drug repurposing; follow-up; genetic analysis; genome wide association study; genome-wide; improved; innovation; multiple omics; novel; preclinical study; psychogenetics; social; success; work-study

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.

项目摘要/摘要 食品药品监督管理局批准了四种治疗酒精使用障碍的药物（AUD） （FDA），许多患者无法从中受益。此外，全基因组关联研究（GWASS） 饮酒和饮酒有问题（PAU；即一种结合AUD诊断和A的表型 有害饮酒的度量）产生了许多影响影响的单核苷酸多态性（SNP） 风险，这些产生的药物靶标几乎没有用于治疗AUD。因此，识别药物靶标有未满足的需求 为了开发新颖和/或重新利用的药物来治疗AUD。最近的研究表明针对 具有遗传支持的疾病机制可以提高药物发育的成功率，并且模块 （即，围绕疾病相关基因的生物网络）富含批准药物的靶标。 因此，影响饮酒和PAU风险及其相关模块的基因可能会产生新的目标 和治疗性重新利用的药物。此外，大型电子健康记录（EHR）的可用性 数据集使探索暴露于FDA批准的药物是否可以改善 除了获得批准的医疗条件（例如AUD），并可能被重新使用。 该建议将以研究团队的先前工作为基础，并利用基因组学的进步并访问 通过VA信息学和计算基础设施（VICCI）到：1）阐明，退伍军人事务（VA）EHR 与饮酒和PAU相关的模块（目标1和3）； 2）确定有前途的重新利用药物 处理aud（目标2）。目标1-2的一般假设是：1）与已识别模块有关的基因 将由众多批准的药物作为目标； 2）在VA EHR中具有足够患者数据的药物， 有证据表明，它们在倾向评分分析中减少饮酒。假设 AIM 3是，分析将确定与使用的最高排名模块 与饮酒和PAU有关。总而言之，该建议结合了精神病遗传和 识别新目标并评估有希望的药物要重新使用的有希望的药物的药物学方法论方法 治疗aud。一种理论，遗传数据驱动的方法，用于选择有希望的FDA批准药物和 然后，使用倾向分数方法在EHR中测试它们，以前尚未在精神病学中进行， 包括aud。 GWA饮酒和PAU的最新进展使该项目成为可能 药物靶标连接，以及用于遗传和其他分析的EHR的种植。这种药物优先级的方法 可以发现在随访临床试验中测试的独特药物，并在临床前进行评估的新靶标 研究。