Identifying Novel Brain Proteins Contributing to PTSD and Alcohol Use Disorder

识别导致创伤后应激障碍和酒精使用障碍的新型脑蛋白

• 批准号: 10253128
• 负责人: Aliza Pham Wingo
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10253128
• 关键词: Address; Alleles; Amygdaloid structure; Anterior; Brain; Brain region; Clinical Trials; Code; Complex; Data; Data Set; Development; Disease; Disease model; Drug Targeting; Funding; Gene Frequency; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic study; Goals; Hippocampus (Brain); Human; Human Genetics; Individual; Major Depressive Disorder; Mediating; Mediation; Mendelian randomization; Mental Depression; Mental Health; Mental disorders; Messenger RNA; Meta-Analysis; Nature; Neurosciences; Nucleus Accumbens; Outcome; Participant; Patients; Personal Satisfaction; Persons; Post-Transcriptional Regulation; Post-Translational Regulation; Post-Traumatic Stress Disorders; Prefrontal Cortex; Proteins; Proteome; Proteomics; Publishing; Quantitative Trait Loci; Regulation; Research Personnel; Role; Single Nucleotide Polymorphism; Site; Susceptibility Gene; Symptoms; Techniques; Testing; Time; Translational Regulation; United States National Institutes of Health; Variant; Veterans; Weight; Work; alcohol use disorder; base; case control; causal variant; cingulate cortex; comorbidity; genetic architecture; genetic testing; genetic variant; genome wide association study; genome-wide; genomic locus; high risk; individualized medicine; insight; mRNA Expression; novel; novel therapeutics; precision medicine; programs; protein biomarkers; protein expression; psychiatric genomics; regional difference; statistics; suicidal risk; therapeutic development; therapeutic target; transcriptome sequencing; transcriptomics

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are among the most prevalent and debilitating psychiatric disorders in U.S. Veterans. They are highly comorbid and have shared genetic susceptibility. Treatments for PTSD or AUD are ineffective in many patients, and comorbid PTSD and AUD are often more difficult to treat and associated with more severe symptoms, higher suicide risk, and poorer outcomes. Thus, the overarching goal of this proposal is to identify brain proteins predisposing to PTSD, AUD, or both as potential promising drug targets to support the development of novel treatments for these disorders. Our proposal builds on insights into the complex genetic architecture of PTSD and AUD gained through large genome-wide association studies (GWAS). GWAS tests allele frequency difference between cases and controls for individual single nucleotide polymorphisms (SNPs) to identify SNPs associated with disease. A genetic locus may have tens to dozens of SNPs associated with the disease. Disentangling which SNPs are important in predisposing to the disease versus those coincidentally associated because they are physically close to important genetic variant sites (i.e., due to linkage) is the next great challenge of human genetics. To address this challenge, several analytical approaches have emerged to integrate information about genetic control of mRNA expression with GWAS results to identify potentially causal genes. To date, these approaches have focused on mRNA expression, but there are two major advantages gained by focusing on protein expression. First, the vast majority of drug targets and biomarkers are proteins. Second, studying brain proteins directly will provide more confidence on the nominated therapeutic targets because mRNAs may not frequently be optimal surrogates for proteins given the complex post-transcriptional, translational, and post- translational regulation. Thus, we propose to leverage human brain proteomes to test the hypothesis that some genetic variants are associated with PTSD or AUD because they modulate brain protein expression in a way that predisposes to PTSD, AUD, or both. To test this hypothesis, we will integrate PTSD and AUD GWAS summary statistics, respectively, from participants of the Million Veteran Program and Psychiatric Genomics Consortium with human brain proteomes using the state-of-the-art analytical techniques to identify genes that modulate brain protein expression to predispose to PTSD, AUD, or both. We aim to identify genes with evidence consistent with being causal in PTSD or AUD, which means that they meet the following three conditions. First, the gene has one or more alleles strongly associated with the disease. Second, the brain protein expression regulated by proximal genetic variants (referred to as cis-regulated brain protein level) is associated with the disease. Third, the cis- regulated brain protein expression mediates the effect of the gene on the disease. The causal inference of this integrative strategy has been experimentally tested and shown to be robust. The first aim of the proposal will focus on merging all available human brain proteomic and genetic data available from our own work and that of our collaborators to estimate effect of SNPs on human brain protein expression. In the second aim, we will integrate PTSD or AUD GWAS summary statistics with the brain protein expression data to identify potentially causal genes for PTSD, AUD, or both. Finally, in the third aim, we will test whether genetic regulation of protein expression for the causal genes identified in Aim 2 is similar in multiple specific brain regions relevant to PTSD or AUD (amygdala, hippocampus, anterior cingulate cortex, and nucleus accumbens). Findings from our proposed studies will identify specific genes and brain proteins as potential promising targets for further mechanistic study to support novel therapeutic development for PTSD, AUD, or both and will have important and long-lasting impact on the mental health and well-being of Veterans.

创伤后应激障碍 (PTSD) 和酒精使用障碍 (AUD) 是最常见的疾病 以及美国退伍军人的衰弱性精神疾病。他们具有高度共病并具有共同的遗传基因 易感性。 PTSD 或 AUD 的治疗对许多患者无效，并且 PTSD 和 AUD 合并症 通常更难以治疗，并伴有更严重的症状、更高的自杀风险和更贫穷的症状 结果。因此，该提案的首要目标是识别易患 PTSD、AUD、 或两者都作为潜在有前途的药物靶点来支持这些疾病的新疗法的开发。 我们的建议建立在对 PTSD 和 AUD 复杂遗传结构的深入了解之上 大型全基因组关联研究（GWAS）。 GWAS 测试病例和病例之间的等位基因频率差异 控制个体单核苷酸多态性 (SNP)，以识别与疾病相关的 SNP。一个 基因位点可能有数十到数十个与该疾病相关的 SNP。理清哪些 SNP 是 与那些巧合相关的疾病相比，它们对于诱发该疾病很重要，因为它们在身体上 靠近重要的遗传变异位点（即由于连锁）是人类遗传学的下一个巨大挑战。 为了应对这一挑战，出现了几种分析方法来整合有关信息 通过 GWAS 结果对 mRNA 表达进行遗传控制，以识别潜在的致病基因。迄今为止，这些 方法主要关注 mRNA 表达，但关注 mRNA 表达有两个主要优势 蛋白质表达。首先，绝大多数药物靶点和生物标志物都是蛋白质。二、研究大脑 直接蛋白质将为指定的治疗靶点提供更多信心，因为 mRNA 可能不会 考虑到复杂的转录后、翻译和后处理过程，它们通常是蛋白质的最佳替代物。 翻译监管。因此，我们建议利用人脑蛋白质组来检验以下假设： 遗传变异与 PTSD 或 AUD 相关，因为它们以某种方式调节大脑蛋白质表达 容易患上 PTSD、AUD 或两者。 为了检验这一假设，我们将分别整合 PTSD 和 AUD GWAS 摘要统计数据， 百万退伍军人计划和精神病基因组学联盟的参与者与人脑蛋白质组 使用最先进的分析技术来识别调节大脑蛋白质表达的基因 易患 PTSD、AUD 或两者。我们的目标是识别具有与因果关系一致的证据的基因 PTSD或AUD，这意味着他们满足以下三个条件。首先，该基因具有一个或多个 等位基因与疾病密切相关。二、近端调控的脑蛋白表达 遗传变异（称为顺式调节脑蛋白水平）与该疾病有关。第三，顺式 受调节的脑蛋白表达介导该基因对疾病的影响。由此得出的因果推论 综合策略已经过实验测试并被证明是稳健的。 该提案的第一个目标将集中于合并所有可用的人脑蛋白质组和遗传数据 我们自己和合作者的工作可用于估计 SNP 对人脑蛋白质的影响 表达。在第二个目标中，我们将把 PTSD 或 AUD GWAS 摘要统计数据与大脑蛋白结合起来 表达数据来识别 PTSD、AUD 或两者的潜在致病基因。最后，在第三个目标中，我们将 测试目标 2 中确定的因果基因的蛋白质表达的遗传调控是否与 与 PTSD 或 AUD 相关的多个特定大脑区域（杏仁核、海马体、前扣带皮层、 和伏隔核）。 我们提出的研究结果将确定具有潜在前景的特定基因和大脑蛋白质 进一步机制研究的目标，以支持针对 PTSD、AUD 或两者的新疗法开发，并将 对退伍军人的心理健康和福祉产生重要而持久的影响。