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 和衰弱性精神疾病的研究他们是高度共病，并有共同的遗传 易感性PTSD或AUD的治疗在许多患者中无效，并且PTSD和AUD共病是 通常更难治疗，并伴有更严重的症状、更高的自杀风险和更贫穷的 结果。因此，这项提议的首要目标是鉴定易患PTSD、AUD、 或两者都作为潜在的有希望的药物靶点，以支持这些疾病的新治疗的开发。 我们的建议建立在对PTSD和AUD复杂遗传结构的深入了解上， 大型全基因组关联研究（GWAS）。GWAS测试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，以鉴定与疾病相关的SNP。一 遗传位点可能有数十到数十个与该疾病相关的SNP。解开哪些SNP是 重要的易感性疾病与那些巧合相关，因为他们是身体 靠近重要的遗传变异位点（即，是人类遗传学的下一个重大挑战。 为了应对这一挑战，出现了几种分析方法，以整合以下信息： 基因控制mRNA表达与GWAS结果，以确定潜在的致病基因。迄今所作的 这些方法都集中在mRNA表达上，但集中在mRNA表达上有两个主要优点。 蛋白质表达首先，绝大多数药物靶标和生物标志物是蛋白质。第二，研究大脑 蛋白质直接将为指定的治疗靶点提供更多的信心，因为mRNA可能不会 通常是蛋白质的最佳替代物，因为复杂的转录后、翻译和后 翻译调节因此，我们建议利用人脑蛋白质组来测试一些假设， 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， 易患创伤后应激障碍澳大利亚焦虑症或两者兼而有之 为了检验这一假设，我们将分别整合PTSD和AUD GWAS汇总统计量， 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鉴定调节大脑蛋白质表达的基因， 易患创伤后应激障碍或澳元兑美元，或两者兼而有之。我们的目标是找出与因果关系一致的基因， PTSD或AUD，这意味着他们符合以下三个条件。首先，该基因具有一个或多个 与疾病密切相关的等位基因。第二，脑蛋白表达受近端 遗传变异（称为顺式调节的脑蛋白水平）与疾病有关。第三，顺-- 受调节的脑蛋白表达介导该基因对疾病的影响。这个因果推论 综合战略已经过实验测试，并显示出强大的。 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遗传数据 从我们自己的工作和我们的合作者的工作中可以估计SNPs对人脑蛋白质的影响 表情在第二个目标中，我们将整合PTSD或AUD GWAS汇总统计与大脑蛋白质 表达数据来鉴定PTSD、AUD或两者的潜在致病基因。最后，在第三个目标中， 测试目标2中鉴定的致病基因的蛋白质表达的遗传调控是否与 与PTSD或AUD相关的多个特定脑区（杏仁核，海马，前扣带皮层， 和细胞核）。 我们提出的研究结果将确定特定的基因和脑蛋白作为潜在的有前途的 进一步机制研究的目标，以支持PTSD，AUD或两者的新治疗开发，并将 对退伍军人的心理健康和福祉产生重要和持久的影响。

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.