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

项目概要/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）以及它们在整个生命周期中的共同发生。AUD 和创伤后应激障碍经常同时发生，合并症与许多负面的临床结果有关，包括 更严重的症状、更差的治疗预后、自杀意念和更差的身体健康。机制 合并症的发病率在很大程度上仍不清楚，但重叠遗传病因学形式的共同风险可能起着重要作用。 作用AUD和PTSD具有中度遗传性，在潜在遗传风险方面重叠，并且在以下方面具有遗传相关性 大型GWAS研究（rG=0.35），尤其是在女性中。除了遗传风险，创伤暴露可能是 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，在这方面， 需要查明创伤增加风险的机制。初步证据显示， 童年创伤影响大脑发育（即，在青春期和青年期观察到的非典型EEG活动 成年期），这反过来又增加了AUD和PTSD的风险。在女性中的影响更为强烈， 有AUD家族史。尽管有这些令人鼓舞的发现，但人们对创伤的影响知之甚少。 青少年和年轻人的大脑发育和AUD和PTSD的风险，没有其他研究检查 这些因素在纵向范式中结合在一起，留下了童年创伤之间复杂的相互作用， 对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 在一个高度翻译的目标集的文献空白。本研究在研究团队前期工作的基础上， 将评估童年创伤对大脑功能纵向轨迹的影响（即，EEG功能 连接）和成人AUD和PTSD的风险，使用来自遗传学合作研究的数据， 酒精中毒的前瞻性研究。接下来，使用来自最大的全基因组关联研究的汇总统计数据， （GWAS）对AUD、AUD相关表型（例如，酒精使用行为）和创伤后应激障碍，我们将阐明遗传 这些表型的因子结构。一种新的多变量遗传方法--基因组结构方程模型 （gSEM），将用于确定因素结构，并将使用由此产生的最佳拟合模型来产生 多基因风险评分（PRS）指示表型之间共有的遗传风险（例如，PTSD），以及 作为每种情况的独特风险。最后，这些PRS指数风险独特和共同的AUD-PTSD将是 整合到儿童创伤、EEG功能连接和成人AUD风险的纵向分析中 和创伤后应激障碍还将研究重要的性别差异。这项研究的结果将揭示这些 这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.