Genetic relationships between PTSD and Alcohol Use Disorder: Integrating GWAS and Deeply Phenotyped Longitudinal data.

项目摘要/摘要 童年创伤暴露，特别是以人际暴力的形式，增加了酗酒的风险 使用障碍(AUD)、创伤后应激障碍(PTSD)及其在一生中共同出现。澳元 创伤后应激障碍和创伤后应激障碍经常同时发生，共病与一系列负面临床结果有关，包括 症状更严重，治疗预后更差，有自杀念头，身体健康状况不佳。机制 合并症的发生率在很大程度上仍不清楚，但重叠的遗传病因形式的共同风险可能会发挥作用 角色。AUD和PTSD具有适度的遗传性，在潜在的遗传风险方面存在重叠，并且在 大规模的GWAS研究(Rg=0.35)，特别是在妇女中。除了遗传风险，接触创伤可能还会 成人AUD和PTSD的共同风险因素，其影响可能因遗传风险而加剧。然而， 需要确定创伤增加风险的机制。初步证据表明 童年创伤影响大脑发育(即在青春期和青春期观察到的非典型脑电活动 成年期)，这反过来又增加了患澳门氏症和创伤后应激障碍的风险。在女性和女性中影响更大 有澳元家族史。尽管有这些令人振奋的发现，但人们对创伤对 青少年和年轻成人的大脑发育与AUD和创伤后应激障碍的风险，并且没有其他研究检验 这些因素在一个纵向范式中结合在一起，留下了童年创伤、 AUD和PTSD的多基因和神经发育风险知之甚少。本研究将填补这些空白 在一套高度翻译的目标中，文学上的空白。建设研究团队的前期工作，本研究 将评估儿童创伤对脑功能纵向轨迹(即脑电功能)的影响 连接性)和成人AUD和PTSD的风险 酒精中毒的前瞻性研究。接下来，使用最大的全基因组关联研究的汇总统计数据 在AUD、AUD相关表型(如饮酒行为)和创伤后应激障碍(PTSD)上，我们将阐明遗传 这些表型的因子结构。一种新的多元遗传方法--基因组结构方程建模 (Gsem)，将用于确定因素结构，并将使用所得到的最佳拟合模型来生成 多基因风险分数(PR)也指示表型之间共享的遗传风险(例如，AUD-PTSD) 作为每种情况下的独特风险。最后，对于澳元-创伤后应激障碍来说，这些独特且常见的PRS索引风险将是 纳入儿童创伤、脑电功能连接性和成人AUD风险的纵向分析 和创伤后应激障碍。重要的性别差异也将被研究。这项研究的结果将有助于揭示这些问题 重要的公共卫生状况，并将对预防和干预工作产生重要影响。

Project Summary/Abstract Childhood trauma exposure, particularly in the form of interpersonal violence, increases risk for alcohol use disorder (AUD), posttraumatic stress disorder (PTSD) and their co-occurrence throughout the lifespan. AUD and PTSD frequently co-occur, and comorbidity is associated with a host of negative clinical outcomes, including greater symptom severity, poorer treatment prognosis, suicidal ideation, and poor physical health. Mechanisms of comorbidity remain largely unknown, but shared risk in the form of overlapping genetic etiology may play a role. AUD and PTSD are moderately heritable, overlap in latent genetic risk, and are genetically correlated in large GWAS studies (rG=0.35), particularly among women. In addition to genetic risk, trauma exposure may be a shared risk factor for adult AUD and PTSD, the impact of which may be exacerbated by genetic risk. However, the mechanisms by which trauma increases risk need to be identified. Preliminary evidence suggests that childhood trauma impacts brain development (i.e., atypical EEG activity observed during adolescence and young adulthood), which in turn increases risk for AUD and PTSD. Effects were more robust among females and those with a family history of AUD. Despite these promising findings, little is known about the influence of trauma on adolescent and young adult brain development and risk for AUD and PTSD, and no other studies have examined these factors together in a longitudinal paradigm, leaving the complex interactions among childhood trauma, polygenic, and neurodevelopmental risk for AUD and PTSD poorly understood. The present study will fill these gaps in the literature in a highly translational set of aims. Building of the research team’s prior work, this study will assess the impact of childhood trauma on longitudinal trajectories of brain functioning (i.e., EEG functional connectivity) and risk for adult AUD and PTSD using data from the Collaborative Study on the Genetics of Alcoholism’s prospective study. Next, using summary statistics from the largest genome wide association studies (GWAS) on AUD, AUD-related phenotypes (e.g., alcohol use behaviors) and PTSD, we will elucidate the genetic factor structure of these phenotypes. A novel multivariate genetic method, genomic Structural Equation Modeling (gSEM), will be used to determine the factor structure, and the resulting best-fit model will be used to produce polygenic risk scores (PRS) that index shared genetic risk between the phenotypes (e.g., AUD-PTSD), as well as unique risk for each condition. Finally, these PRS indexing risk unique and common for AUD-PTSD will be integrated into the longitudinal analyses of childhood trauma, EEG functional connectivity, and risk for adult AUD and PTSD. Important sex differences will also be examined. Results from this study will shed light on these important public health conditions and will yield important implications for prevention and intervention efforts.