Longitudinal neuroimaging and statistical genetics modeling of substance use and trauma-related phenotypes

物质使用和创伤相关表型的纵向神经影像和统计遗传学模型

• 批准号: 10592238
• 负责人: Daniel Bustamante
• 金额: $ 2.96万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-01-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592238
• 关键词: Adolescence; Adolescent; Adult; American; Anterior; Area; Award; Brain; Brain region; Child; Childhood; Clinical; Community Surveys; Complex; Conduct Disorder; Data; Development; Diagnostic; Disease; Environmental Risk Factor; Equation; Etiology; Exposure to; Feeling suicidal; Frequencies; Genetic; Genetic Models; Genetic Research; Goals; Health; Heritability; Hippocampus; Individual; Interdisciplinary Study; Knowledge; Left; Life; Link; Linkage Disequilibrium; Magnetic Resonance Imaging; Mediating; Methods; Mission; Modeling; Molecular; Molecular Genetics; National Institute of Drug Abuse; National Research Service Awards; Outcome; Participant; Phenotype; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevention; Process; Psychopathology; Public Health; Research; Risk; Risk Factors; Role; Sampling; Scientific Advances and Accomplishments; Single Nucleotide Polymorphism; Site; Social Functioning; Structure; Substance Addiction; Substance Use Disorder; Symptoms; Testing; Time; Training; Trauma; Twin Multiple Birth; Twin Studies; Variant; Violence; Youth; adverse outcome; aged; brain volume; cingulate cortex; clinical application; cognitive development; comorbidity; compliance behavior; cost; early adolescence; experience; genetic analysis; genetic architecture; genome wide association study; genome-wide; improved; insight; interest; intervention program; molecular phenotype; multimodality; neuroimaging; polygenic risk score; recruit; serial imaging; socioeconomics; statistics; substance use; trait; traumatic event; treatment program; young adult

PROJECT SUMMARY Childhood and early adolescence are especially vulnerable developmental stages where experiencing traumatic events (TEs) would increase the liability and risk for developing posttraumatic stress disorders (PTSD) and substance use (SU) disorder (SUD) later in life. These phenotypes frequently co-occur, and this comorbidity is associated with increased negative outcomes (e.g. decreased social function and treatment compliance, increased risk for violence and suicidal ideation/attempts). Given the complex and multifactorial etiology of these conditions, there is a need for multimethod studies aimed at increasing the understanding of their etiology including genetic and neurodevelopmental factors. Thus far, studies investigating the genetic factors and brain regions of interest (ROIs) thought to influence these phenotypes have largely focused on adults and the majority have been cross-sectional. For this reason, we will use a large (N=11,878) longitudinal sample (Adolescent Brain Cognitive Development [ABCD] study, site-PIs: Drs. Neale and Bjork) to investigate, via Aim 1, the occurrence and type of TEs, other risk factors (e.g., conduct disorder symptoms, parental style; see Research Strategy C.3 section), and their influence on PTSD-symptoms and SU-phenotypes development from childhood to early adolescence. Aim 2 will utilize structural magnetic resonance imaging longitudinal data to estimate statistics of the mediational role of alterations of volume of brain ROIs on the trajectories of PTSD-symptoms and SU- phenotypes. Finally, as SUD and PTSD are moderately heritable, Aim 3 will assess the genetic architecture (e.g. GWAS), generate and use polygenic risk scores to investigate the etiology, trajectories, strength and direction of the relationships across time influencing the early signs and development of PTSD-symptoms and SU- phenotypes. Both molecular genetic and phenotypic analyses (including GCTA, LDSC, Cross-Lagged Panel Analysis, Genome-Wide Structural Equation Modeling) will be applied. This proposal has four training goals to be met via a multi-modal training plan. The first training goal is to develop a deeper scientific knowledge and expertise in PTSD and SUD phenotypes. Second is to become knowledgeable in neuroimaging research and its intersection with genetics and psychopathology. The third goal is to expand proficiency in advanced molecular and statistical genetics modeling. Fourth is to increase professional development training that will enhance academic proficiency. This project is intended to extend the understanding of the contribution of etiological factors (genetic, neurodevelopmental, environmental) and processes involved in the development of PTSD- symptoms and SU-phenotypes during childhood and early adolescence, and offer insights for clinical applications—strategic prevention and treatment of PTSD and SUD. This NRSA proposal aligns with the mission of the National Institute on Drug Abuse (NIDA) on advancing scientific research, by investigating the etiology, trajectories and mechanisms of PTSD-symptoms and SU-phenotypes longitudinally in understudied developmental stages. It also aims to influence the improvement of individual and collective health.

项目概要 童年和青春期早期是特别脆弱的发展阶段，经历 创伤事件（TE）会增加患创伤后应激障碍（PTSD）的责任和风险 和晚年物质使用障碍 (SU)。这些表型经常同时出现，并且这种共病 与负面结果增加相关（例如社会功能和治疗依从性下降， 暴力和自杀意念/企图的风险增加）。鉴于这些疾病的病因复杂且多因素 条件下，需要进行多种方法研究，旨在增加对其病因学的了解 包括遗传和神经发育因素。迄今为止，研究调查了遗传因素和大脑 被认为影响这些表型的感兴趣区域（ROI）主要集中在成年人和大多数人身上 已经是横断面的。因此，我们将使用一个大的（N=11,878）纵向样本（青少年大脑 认知发展 [ABCD] 研究，现场 PI：博士。 Neale 和 Bjork）通过目标 1 调查该事件 TE 的类型、其他风险因素（例如行为障碍症状、父母风格；参见研究策略 C.3） 部分），以及它们对从儿童期到早期的 PTSD 症状和 SU 表型发展的影响 青春期。目标 2 将利用结构磁共振成像纵向数据来估计统计数据 大脑 ROI 体积变化对 PTSD 症状和 SU- 轨迹的中介作用 表型。最后，由于 SUD 和 PTSD 具有中等遗传性，目标 3 将评估遗传结构（例如 GWAS），生成并使用多基因风险评分来研究病因、轨迹、强度和方向 跨时间的关系影响 PTSD 症状和 SU- 的早期症状和发展 表型。分子遗传学和表型分析（包括 GCTA、LDSC、Cross-Lagged Panel 将应用分析（全基因组结构方程模型）。该提案有四个培训目标 通过多模式培训计划来满足。第一个培训目标是发展更深入的科学知识和 PTSD 和 SUD 表型方面的专业知识。其次是了解神经影像学研究及其相关知识 遗传学和精神病理学的交叉点。第三个目标是提高先进分子技术的熟练程度 和统计遗传学模型。四是加大专业发展培训力度 学术能力。该项目旨在加深对病因学贡献的理解 参与 PTSD 发展的因素（遗传、神经发育、环境）和过程 儿童期和青春期早期的症状和 SU 表型，并为临床提供见解 应用——PTSD和SUD的战略预防和治疗。 NRSA 的这项提案符合其使命 国家药物滥用研究所（NIDA）通过调查病因来推进科学研究， 纵向研究中 PTSD 症状和 SU 表型的轨迹和机制 发展阶段。它还旨在影响个人和集体健康的改善。