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）是最普遍的 并使美国退伍军人的精神疾病使人衰弱。它们是高度合并的，并且共享了遗传 敏感性。在许多患者中，PTSD或AUD治疗无效，并且合并症PTSD和AUD是 通常更难以治疗，并与更严重的症状，更高的自杀风险和较差相关 结果。因此，该提案的总体目标是确定易受PTSD，AUD，AUD， 或两者都是潜在的有希望的药物靶标，以支持这些疾病的新型治疗方法。 我们的建议基于对PTSD复杂遗传结构的见解，并通过 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 单个单核苷酸多态性（SNP）的对照以识别与疾病相关的SNP。一个 遗传基因座可能具有数十个与该疾病相关的SNP。解开哪个SNP是 对于疾病而言，与偶然相关的疾病很重要，因为它们在物理上是 接近重要的遗传变异位点（即由于联系）是人类遗传学的下一个重大挑战。 为了应对这一挑战，已经出现了几种分析方法来整合有关的信息 用GWAS对mRNA表达的遗传控制结果，以鉴定潜在的因果基因。迄今为止，这些 方法集中于mRNA表达，但是专注于 蛋白表达。首先，绝大多数药物靶标和生物标志物是蛋白质。其次，研究大脑 蛋白质直接将对提名的治疗靶标提供更多信心，因为mRNA可能不会 考虑到复杂的转录后，翻译和后的复杂的蛋白质，通常是蛋白质的最佳替代物 翻译法规。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脑蛋白表达 易于PTSD，AUD或两者兼有。 为了检验这一假设，我们将分别从 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织 使用最先进的分析技术鉴定调节脑蛋白表达的基因 易感PTSD，AUD或两者兼而有之。我们旨在识别具有与因果关系一致的证据的基因 PTSD或AUD，这意味着它们符合以下三个条件。首先，该基因有一个或多个 等位基因与该疾病密切相关。其次，由近端调节的脑蛋白表达 遗传变异（称为顺式调节的脑蛋白水平）与该疾病有关。第三，顺式 - 调节的脑蛋白表达介导基因对疾病的影响。这一点的因果推断 综合策略已经过实验测试并证明是健壮的。 该提案的第一个目的将集中于合并所有可用的人脑蛋白质组学和遗传数据 从我们自己的工作和合作者的工作中获得估计SNP对人脑蛋白的影响 表达。在第二个目标中，我们将将PTSD或AUD GWAS摘要统计数据与脑蛋白相结合 表达数据以识别PTSD，AUD或两者的潜在因果基因。最后，在第三个目标中，我们将 测试在AIM 2中鉴定出的因果基因的蛋白质表达的遗传调节是否相似 与PTSD或AUD相关的多个特定大脑区域（杏仁核，海马，前扣带回皮层， 和伏隔核）。 我们提出的研究的发现将确定特定的基因和脑蛋白是潜在的有希望的 进一步机械研究的目标，以支持PTSD，AUD或两者的新型治疗发展，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。