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

酒精使用障碍和创伤后应激障碍的遗传和学习机制重叠

• 批准号: 9920643
• 负责人: Christina M Sheerin
• 金额: $ 16.78万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920643
• 关键词: Address; Alcohol Phenotype; Alcohols; Area; Attention; Clinical; Complex; Data; Data Set; Development; Diagnosis; Diagnostic; Disease; Environment; Epidemiology; Etiology; Extinction (Psychology); Fright; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genetic Techniques; Genetic study; Glean; Goals; Heritability; Knowledge; Laboratories; Laboratory Study; Learning; Link; Literature; Maintenance; Measurement; Measures; Mentored Research Scientist Development Award; Mentorship; Modeling; Molecular; Molecular Genetics; National Institute on Alcohol Abuse and Alcoholism; Outcome; Phenotype; Plant Roots; Population; Post-Traumatic Stress Disorders; Prevention; Procedures; Process; Psychophysiology; Research; Research Priority; Research Support; Resistance; Risk; Sampling; Series; Severities; Single Nucleotide Polymorphism; Substance Use Disorder; Symptoms; Training; Translating; Trauma; Twin Studies; Variant; Work; addiction; alcohol comorbidity; alcohol related problem; alcohol use disorder; base; comorbidity; conditioned fear; conditioning; disorder risk; experience; genetic association; genetic epidemiology; genome wide association study; genome-wide; improved; interest; laboratory experiment; large scale data; molecular scale; multidisciplinary; multimodality; outcome forecast; polygenic risk score; programs; psychiatric genomics; psychogenetics; responsible alcohol use; risk sharing; skills; statistical learning; trait; trauma exposure

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.

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： 创伤经常合并，这种合并症与更严重的症状相关， 预后较差。因此，努力更好地了解这些疾病的病因对于减少 消极的结果和改善预防和治疗工作，因为在这方面仍有许多未知数。 病因学和共同发生的机制。最近的研究发现，除了 表型是中度遗传的，它们的潜在遗传风险有一定程度的重叠。 此外，有理由表明，与创伤后应激障碍有关的恐惧学习机制也可能 与AUD相关。需要进一步研究的领域包括鉴定分子变异 负责AUD/PTSD共病，并将恐惧学习模型扩展到AUD和共病 AUD/PTSD人群。统计程序的发展提供了利用基因组的能力- 广泛的关联数据来回答关于这些共享分子基础的关键问题。总体 K 01提案的目标有三个。首先，该研究旨在利用现有的大规模全基因组数据 来自精神病基因组学联盟（PGC; PTSD和物质使用障碍工作组）， 通过基于双变量单核苷酸多态性（SNP）的遗传力模型检查分子重叠， 并确定来自每种疾病的多基因风险评分（PRS）是否预测另一数据集中的病例状态。 第二，将在创伤暴露患者中使用恐惧条件反射范式进行临床实验室研究。 无诊断对照、AUD、PTSD和合并AUD/PTSD诊断组的样本，以确定 学习上的缺陷是共同的。最后，探索性目标将使用PGC数据的PRS评分， 在实验室样本中生成风险评分，以检查是否存在与条件反射缺陷的遗传关联。 为了实现这些目标，候选人和多学科导师团队制定了一个 一个全面的培训计划，其中规定了一系列的培训和研究目标。这些目标将 将AUD和PTSD的流行病学和遗传学、分子和统计遗传学 技术，并进行临床实验室范例使用遗传和心理生理措施。 这一培训和由此产生的调查结果将利用现有的专门知识，并提供额外的重点培训 允许开发一个多模式研究计划，使用大规模的遗传关联， 研究结果开发机制为重点的实验室研究，告知发展和维护 这个复杂的演示。拟议的研究代表了对推进 我们对AUD和PTSD的复杂和频繁共病表型的理解。体制 环境是理想的候选人的目标，发展一个独立的研究路线，最终目的是 减少酒精相关问题的负担，与NIAAA的研究重点一致。