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.

项目概要/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，虽然全基因组关联研究（GWAS） 饮酒和有问题的饮酒（PAU；即结合了 AUD 诊断和酒精滥用的表型） 有害饮酒的衡量标准）已产生许多显着的单核苷酸多态性（SNP），影响 风险，这些已经产生了很少的治疗 AUD 的药物靶点。因此，确定药物靶点的需求尚未得到满足 用于开发治疗 AUD 的新型和/或重新用途药物。最近的研究表明，目标 具有遗传支持的疾病机制可以提高药物开发的成功率，并且该模块 （即围绕疾病相关基因的生物网络）针对已批准药物的靶点进行了丰富。 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目标 以及用于治疗再利用的药物。此外，大型电子健康记录（EHR）的可用性 数据集使得探索接触 FDA 批准的药物是否可以改善 除获得批准的医疗条件外，例如 AUD，并可能被重新利用。 该提案将建立在研究团队之前的工作基础上，并利用基因组学的进步和获取 退伍军人事务部 (VA) EHR 通过 VA 信息学和计算基础设施 (VINCI) 来：1) 阐明 与饮酒和 PAU 相关的模块（目标 1 和 3）； 2) 确定有希望重新利用的药物 治疗 AUD（目标 2）。目标 1-2 的一般假设是：1) 已识别模块中涉及的基因 将成为众多批准药物的目标； 2) VA EHR 中具有足够患者数据的药物， 在倾向评分分析中将有证据表明它们可以减少饮酒量。假设为 目标 3 是分析将确定排名靠前的模块，这些模块针对生物过程进行了丰富 与饮酒量和 PAU 的相关性。总之，该提案结合了精神病学遗传和 药物流行病学方法来识别新靶点并评估有希望重新利用的药物 治疗澳元。一种非理论的、遗传数据驱动的方法来选择有前途的 FDA 批准的药物和 然后使用倾向评分方法在电子病历中对它们进行测试，这在精神病学中是没有做过的， 包括澳元。该项目是由于酒精消费和 PAU 的 GWAS 的最新进展而成为可能的， 药物靶标链接，以及用于遗传和其他分析的 EHR 培养。这种药物优先排序方法 可以发现在后续临床试验中测试的独特药物以及在临床前评估的新靶点 研究。