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

PTSD 和酒精使用障碍之间的遗传关系：整合 GWAS 和深度表型纵向数据。

基本信息

批准号：
10672457
负责人：
ANANDA B AMSTADTER
金额：
$ 53.35万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672457
关键词：
Adolescence Adolescent and Young Adult Adult Adult Children Affect Age Alcohol abuse Alcohol consumption Area Behavior Big Data Binding Brain Brain-Derived Neurotrophic Factor Candidate Disease Gene Cannabis Childhood Clinical Complex Consumption Data Data Set Development Disease Distal Elderly Electroencephalography Environmental Risk Factor Equation Etiology Exhibits Exposure to Family Family history of Feeling suicidal Female Frequencies Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Techniques Genomics Growth Heritability Hippocampus Intercept Interpersonal Violence Intervention Interview Investigation Knowledge Literature Longevity Longitudinal Studies Measurement Measures Mental Depression Methodology Methods Modeling Molecular Neurobiology Neurocognitive Neurocognitive Deficit Nicotine Outcome Participant Pathway interactions Phenotype Post-Traumatic Stress Disorders Prevention Prognosis Prospective Studies Psychopathology Public Health Research Retrospective Studies Risk Risk Factors Sampling Scoring Method Severities Sex Differences Statistical Methods Structure Symptoms Trauma Variant Woman Work alcohol risk alcohol use disorder comorbidity design drinking genetics of alcoholism genome wide association study genome-wide indexing longitudinal analysis neural neurodevelopment novel pediatric trauma physical conditioning polygenic risk score risk sharing sex sexual trauma statistics substance use trait trauma exposure young adult young adult alcohol use

项目摘要

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.

项目概要/摘要童年时期的创伤暴露，尤其是人际暴力形式，会增加酗酒的风险使用障碍（AUD）、创伤后应激障碍（PTSD）及其在整个生命周期中的共同发生。和 PTSD 经常同时发生，并且合并症与许多负面的临床结果相关，包括症状更严重、治疗预后更差、自杀意念和身体健康状况不佳。合并症的发病率在很大程度上仍然未知，但以重叠遗传病因学形式出现的共同风险可能会发挥重要作用 AUD 和 PTSD 具有中等遗传性，潜在遗传风险重叠，并且在遗传方面具有相关性。大型 GWAS 研究（rG=0.35），特别是在女性中。除了遗传风险之外，创伤暴露也可能是影响因素。成人 AUD 和 PTSD 的共同危险因素，遗传风险可能会加剧其影响。需要确定创伤增加风险的机制。童年创伤影响大脑发育（即在青春期和青年时期观察到的非典型脑电图活动）成年期），这反过来又增加了 AUD 和 PTSD 的风险，对女性和女性的影响更为明显。尽管有这些令人鼓舞的发现，但人们对创伤对疾病的影响知之甚少。青少年和年轻人的大脑发育以及 AUD 和 PTSD 的风险，并且没有其他研究进行过检验这些因素在一个纵向范式中结合在一起，留下了童年创伤之间复杂的相互作用，目前对 AUD 和 PTSD 的多基因和神经发育风险知之甚少。本研究旨在弥补研究团队之前工作中的一系列高度转化性目标中的文献空白。将评估童年创伤对大脑功能纵向轨迹的影响（即脑电图功能连接性）以及成人 AUD 和 PTSD 的风险，使用来自遗传学合作研究的数据接下来，使用最大的全基因组关联研究的汇总统计数据进行酒精中毒的前瞻性研究。（GWAS）关于 AUD、AUD 相关表型（例如饮酒行为）和 PTSD，我们将阐明遗传因素这些表型的因子结构。一种新颖的多变量遗传方法，基因组结构方程模型。（gSEM），将用于确定因子结构，所得的最佳拟合模型将用于生成多基因风险评分 (PRS)，它还索引了表型之间共有的遗传风险（例如 AUD-PTSD）最后，这些针对 AUD-PTSD 的独特且常见的 PRS 指数风险将是：纳入儿童创伤、脑电图功能连接和成人 AUD 风险的纵向分析这项研究的结果也将揭示这些重要的性别差异。重要的公共卫生状况，将对预防和干预工作产生重要影响。