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

项目摘要 童年和青春期早期是特别脆弱的发展阶段， 创伤性事件（TEs）会增加患创伤后应激障碍（PTSD）的责任和风险 在生活中，物质使用（SU）障碍（SUD）这些表型经常同时出现， 与增加的负面结果（例如，社会功能和治疗依从性降低， 暴力和自杀意念/企图的风险增加）。鉴于这些复杂和多因素的病因， 条件下，有必要进行多方法研究，旨在增加其病因学的理解 包括遗传和神经发育因素。到目前为止，研究遗传因素和大脑 被认为影响这些表型的感兴趣区域（ROI）主要集中在成年人身上， 都是横向的。出于这个原因，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，研究中心PI：Drs. Neale和Bjork），通过目标1调查 和TE类型，其他风险因素（例如，行为障碍症状，父母风格;见研究策略C.3 部分），以及它们对PTSD症状和SU表型从儿童期到早期发展的影响 青春期目标2将利用结构磁共振成像纵向数据来估计 脑ROI体积的改变对PTSD症状和SU-1轨迹的中介作用。 表型最后，由于SUD和PTSD具有中度遗传性，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调查病因、轨迹、强度和方向 影响PTSD症状和SU早期体征和发展的时间关系 表型分子遗传学和表型分析（包括GCTA、LDSC、交叉滞后组 分析，全基因组结构方程模型）。该计划有四个培训目标， 通过多模式培训计划来满足。第一个培训目标是发展更深层次的科学知识， 创伤后应激障碍和SUD表型方面的专业知识。第二是成为神经影像学研究及其 遗传学和精神病理学的交叉点第三个目标是提高对先进分子生物学的熟练程度， 和统计遗传学建模。第四是增加专业发展培训， 学术能力。该项目旨在扩大对病因学贡献的理解， 因素（遗传，神经发育，环境）和过程参与PTSD的发展- 症状和SU-表型在儿童期和青春期早期，并提供见解的临床 PTSD和SUD的战略性预防和治疗。NRSA的这一建议与使命一致 国家药物滥用研究所（NIDA）通过调查病因， PTSD症状和SU表型的纵向轨迹和机制 发育阶段它还旨在影响个人和集体健康的改善。

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.