Overlap in genetic and learning-based mechanisms for alcohol use disorder and posttraumatic stress disorder

项目摘要 酒精使用障碍(AUD)和创伤后应激障碍(PTSD)是以下常见结果 经常合并的创伤，这种共病与更严重的症状和 预后较差。因此，努力更好地了解这些疾病的病因对于减少 消极结果和改善预防和治疗努力，因为关于 它们共同发生的病因学和机制。最近的研究发现，除了这两种 由于表型具有适度的遗传性，它们的潜在遗传风险有一定程度的重叠。 此外，有理由认为，经常与创伤后应激障碍相关的恐惧学习机制也可能 与澳元联系在一起。需要进一步研究的领域包括分子变异的鉴定 对AUD/PTSD共病负责，并将恐惧学习模型扩展到AUD和共病 澳大利亚/创伤后应激障碍人群。统计程序的发展为利用基因组-- 广泛的关联数据，以回答关于这些共同的分子基础的关键问题。最重要的是 这项K01提案的目标有三个。首先，这项研究旨在利用现有的大规模全基因组数据 从精神病基因组学联盟(PGC；创伤后应激障碍和物质使用障碍工作组)到 通过基于双变量单核苷酸多态(SNP)的遗传力模型检查分子重叠， 并确定来自每个疾病的多基因风险分数(PRS)是否预测另一个数据集中的病例状态。 其次，一项临床实验室研究将在创伤暴露的患者中使用恐惧条件反射范式进行。 无诊断对照、AUD、PTSD和AUD/PTSD共病诊断组样本，以确定是否 学习上的缺陷是共同的。最后，一个探索性的目标是使用PGC数据中的PRS分数来 在实验室样本中生成风险分数，以检查是否存在遗传与条件反射缺陷的关联。 为了实现这些目标，候选人和多学科指导团队制定了一项 全面的培训计划，列出了一系列培训和研究目标。这些目标将 纳入有关澳大利亚和创伤后应激障碍的流行病学和遗传学、分子遗传学和统计遗传学的培训 使用遗传学和心理生理学措施进行临床实验室范例的技术和指导。 这一培训和结果将利用现有的专业知识，并提供额外的、重点突出的培训 允许开发使用大规模基因关联的多模式研究计划 开发以机制为重点的实验室研究的结果，为开发和维护提供信息 这个复杂的演示文稿。拟议的研究是对推动 我们对复杂且经常并存的AUD和PTSD表型的理解。体制上的 环境是候选人发展一条独立研究路线的理想环境，最终目标是 减少酒精相关问题的负担，这与NIAAA的研究优先事项一致。

Project Summary Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are common outcomes following trauma that are frequently comorbid, and this comorbidity is associated with greater symptom severity and poorer prognosis. Thus, efforts to better understand the etiology of these conditions is important for decreasing negative outcomes and improving prevention and treatment efforts, as much is still unknown regarding the etiology and mechanisms involved in their co-occurrence. Recent research has found that in addition to both phenotypes being moderately heritable, there is a modest degree of overlap in their latent genetic risk. Moreover, there is reason to suggest that fear-learning mechanisms frequently associated with PTSD may also be associated with AUD. Areas in need of further research include identification of molecular variation responsible for AUD/PTSD comorbidity, and extension of fear-learning models to AUD and comorbid AUD/PTSD populations. Developments in statistical procedures have afforded the ability to leverage genome- wide association data to answer key questions about these shared molecular underpinnings. The overarching goals of this K01 proposal are threefold. First, the study aims to use existing large-scale genome-wide data from the Psychiatric Genomics Consortium (PGC; PTSD and Substance Use Disorders workgroups) to examine the molecular overlap via bivariate single nucleotide polymorphism (SNP)-based heritability models, and determine if the polygenic risk score (PRS) from each disorder predicts case status in the other dataset. Second, a clinical laboratory study will be conducted using fear-conditioning paradigms in a trauma-exposed sample of diagnosis free controls, AUD, PTSD, and comorbid AUD/PTSD diagnostic groups to determine if deficits in learning are shared. Finally, an exploratory aim will use the PRS scores from the PGC data to generate risk scores in the lab sample to examine if there is a genetic association with conditioning deficits. To achieve these aims, the candidate and multidisciplinary mentorship team have developed a comprehensive training plan that delineates a series of training and research goals. These goals will incorporate training in the epidemiology and genetics of AUD and PTSD, molecular and statistical genetics techniques, and conduct of clinical laboratory paradigms using genetic and psychophysiological measures. This training and resultant findings will capitalize on existing expertise and provide additional, focused training to allow for the development of a multimodal research program that uses large-scale genetic association findings to develop mechanism-focused laboratory studies that inform upon the development and maintenance of this complex presentation. The proposed research represents an important contribution towards advancing our understanding of the complicated and frequently comorbid phenotypes of AUD and PTSD. The institutional environment is ideal for the candidate's goal of developing an independent research line that ultimately aims to decrease the burden of alcohol-related problems, consistent with NIAAA research priority.