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。

• 批准号: 10418931
• 负责人: ANANDA B AMSTADTER
• 金额: $ 55.52万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 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/10418931
• 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; Cross-Sectional Studies; 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 (Brain); Intercept; Interpersonal Violence; Intervention; Interview; Investigation; Knowledge; Light; Literature; Longevity; Longitudinal Studies; Measurement; Measures; Mental Depression; Methodology; Methods; Modeling; Molecular; Neurobiology; Neurocognitive; Neurocognitive Deficit; Nicotine; Outcome; Participant; Pathway interactions; Phenotype; Play; Post-Traumatic Stress Disorders; Prevention; Prognosis; Prospective Studies; Psychopathology; Public Health; Research; Retrospective Studies; Risk; Risk Factors; Role; Sampling; Scoring Method; Severities; Sex Differences; Statistical Methods; Structure; Symptoms; Trauma; Variant; Woman; alcohol risk; alcohol use disorder; comorbidity; design; drinking; genetics of alcoholism; genome wide association study; genome-wide; indexing; longitudinal analysis; neurodevelopment; novel; pediatric trauma; physical conditioning; polygenic risk score; relating to nervous system; risk sharing; sex; sexual trauma; statistics; substance use; trait; trauma exposure; work-study; young adult; young adult alcohol use

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.

项目摘要/摘要 童年创伤暴露，特别是在人际暴力的形式中，增加了酒精的风险 使用障碍（AUD），创伤后应激障碍（PTSD）及其在整个生命周期中的同时出现。奥德 和PTSD经常共发生，合并症与许多负面临床结果有关，包括 更大的症状严重程度，治疗预后较差，自杀想法和身体健康状况不佳。机制 合并症仍然很大未知，但是以重叠遗传病因的形式共同的风险可能会发挥作用 角色。 AUD和PTSD是中等遗传的，在潜在遗传风险中重叠，并且在遗传上相关 大型GWAS研究（RG = 0.35），尤其是在女性中。除遗传风险外，创伤暴露可能是 成人AUD和PTSD的共同风险因素，其影响可能会因遗传风险而加剧。然而， 需要确定创伤增加风险的机制。初步证据表明 儿童创伤会影响大脑发育（即青少年和年轻人观察到的非典型脑电图活性 成年），这反过来增加了AUD和PTSD的风险。女性和那些人的影响更加强大 有一个澳元的家族史。尽管有这些希望的发现，但对创伤的影响知之甚少 青少年和年轻的成人脑发育以及AUD和PTSD的风险，没有其他研究检查 这些因素以纵向范式共同，使童年创伤之间的复杂相互作用， AUD和PTSD的多基因和神经发育风险不佳。本研究将填补这些 文献中的差距是一组高度翻译的目标。研究团队的先前工作，这项研究 将评估儿童创伤对脑功能纵向轨迹的影响（即脑电图功能 连通性）和成人AUD和PTSD的风险使用来自协作研究的数据 酒精中毒的前瞻性研究。接下来，使用最大基因组关联研究的摘要统计数据 （GWAS）在AUD，AUD相关表型（例如，酒精使用行为）和PTSD上，我们将阐明通用性 这些表型的因子结构。一种新型的多元遗传方法，基因组结构方程建模 （GSEM）将用于确定因子结构，最佳拟合模型将用于生产 多基因风险评分（PR），指数在表型（例如AUD-PTSD）之间具有遗传风险 作为每个条件的独特风险。最后，这些PRS索引风险独特而通用的AUD-PTSD将是 集成到儿童创伤，脑电图功能连通性和成人AUD风险的纵向分析中 和PTSD。还将检查重要的性别差异。这项研究的结果将阐明这些 重要的公共卫生状况，将对预防和干预工作产生重要影响。