Identifying Novel Brain Proteins Contributing to PTSD and Alcohol Use Disorder

创伤后应激障碍(PTSD)和酒精使用障碍(AUD)是最普遍的 以及美国退伍军人的衰弱精神障碍。他们高度共病，并具有相同的基因 敏感度。PTSD或AUD的治疗在许多患者中无效，而PTSD和AUD并存 通常更难治疗，并与更严重的症状、更高的自杀风险和更贫穷相关 结果。因此，这项提议的首要目标是确定大脑中易患创伤后应激障碍、AUD、 或者两者都是潜在的有希望的药物靶点，以支持这些疾病的新疗法的开发。 我们的建议建立在对创伤后应激障碍和澳门氏症复杂遗传结构的洞察基础上，通过 大型全基因组关联研究(GWAS)。Gwas检测病例和患者之间的等位基因频率差异 个体单核苷酸多态(SNPs)对照，以确定与疾病相关的SNPs。一个 遗传基因座可能有数十到几十个与这种疾病相关的SNP。弄清楚哪些SNP是 与那些巧合相关的人相比，他们在易患疾病方面很重要，因为他们在身体上 接近重要的遗传变异位点(即由于连锁)是人类遗传学面临的下一个重大挑战。 为了应对这一挑战，出现了几种分析方法来整合关于以下方面的信息 基因控制的基因表达与GWAS的结果，以确定潜在的原因基因。迄今为止，这些 各种方法都集中在mRNA的表达上，但专注于 蛋白质表达。首先，绝大多数药物靶标和生物标记物是蛋白质。第二，研究大脑 蛋白质直接将对提名的治疗靶点提供更多的信心，因为mRNAs可能不 通常是蛋白质的最佳替代品，因为复杂的转录后，翻译和后- 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 基因变异与PTSD或AUD有关，因为它们在某种程度上调节大脑蛋白质的表达 这容易导致创伤后应激障碍、澳门氏症或两者兼而有之。 为了验证这一假设，我们将分别集成PTSD和AUD Gwas汇总统计数据，从 百万退伍军人计划和人类脑蛋白质组精神病学基因组联合会的参与者 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 易患创伤后应激障碍、澳门氏症或两者兼有。我们的目标是用与疾病因果关系相一致的证据来鉴定基因 创伤后应激障碍或澳元，这意味着他们满足以下三个条件。首先，该基因有一个或多个 与这种疾病密切相关的等位基因。第二，近端基因调控的脑内蛋白表达 基因变异(被称为顺式调节的大脑蛋白质水平)与疾病有关。第三，独联体-- 受调控的大脑蛋白表达介导了该基因对疾病的影响。这一点的因果推论 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在合并所有可用的人脑蛋白质组和基因数据 可从我们自己和我们的合作者的工作中估计SNPs对人脑蛋白质的影响 表情。在第二个目标中，我们将把创伤后应激障碍或AUD Gwas汇总统计数据与大脑蛋白质相结合 表达数据，以确定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中确定的致病基因的蛋白质表达的遗传调节是否与 与PTSD或AUD相关的多个特定脑区(杏仁核、海马体、前扣带回皮质、 和伏隔核)。 我们提出的研究结果将确定特定的基因和大脑蛋白是潜在的有希望的 进一步机制研究的目标，以支持创伤后应激障碍和/或AUD的新治疗开发，并将 对退伍军人的心理健康和福祉有重要和持久的影响。

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.