Trauma and Genomics Modulate Brain Structure across Common Psychiatric Disorders

创伤和基因组学调节常见精神疾病的大脑结构

• 批准号: 9389397
• 负责人: MARK W LOGUE
• 金额: $ 47.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9389397
• 关键词: Adult; Amygdaloid structure; Anxiety Disorders; Architecture; Area; Arousal; Automobile Driving; Behavior; Big Data; Bioinformatics; Bipolar Disorder; Brain; Child; Childhood; Clinical Paths; Collaborations; Corpus striatum structure; Data; Disease; Environment; Evaluation; Exposure to; Extinction (Psychology); Fright; Gene Expression; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Goals; Heritability; Hippocampus (Brain); Human; Individual; Intervention; Lead; Life; Magnetic Resonance Imaging; Measures; Medial; Memory; Mental Depression; Mental disorders; Meta-Analysis; Methodology; Molecular; Molecular Genetics; Mood Disorders; Morphology; Neurobiology; Participant; Pathogenesis; Pathology; Pathway interactions; Phenotype; Post-Traumatic Stress Disorders; Psychopathology; Research Domain Criteria; Risk; Risk Factors; Sampling; Shapes; Site; Structure; Surface; Symptoms; Thick; Trauma; abuse neglect; base; brain pathway; clinical phenotype; deep sequencing; endophenotype; gene discovery; genetic risk factor; genetic variant; genome wide association study; inattention; neuroimaging; new therapeutic target; pediatric trauma; psychogenetics; psychological trauma; tool; white matter; whole genome; working group

ABSTRACT Exposure to trauma and abuse during childhood, a critical neurodevelopmental period, is a major risk factor for adult psychopathology. However, not all children exposed to childhood trauma will develop adult psychopathology. Variability in the risk for trauma-related pathology is expected to arise in part from genetic susceptibility. Several genes have recently been identified that interact with childhood trauma to increase rates of anxiety and mood disorders in adulthood. This risk can be more easily detected by examining endophenotypes such as brain measures obtained from MRI because of a simpler underlying genetic architecture with fewer individual genes or pathways than the multiple factors driving overall risk for psychopathology. Understanding the molecular-genetic contributors to brain structure that conspire with early-life environment (psychological trauma) and lead to adult psychopathology, will require large-scale collaborative efforts which harness big-data methodologies. Our goal is to conduct a GWAS of relevant structural brain measures in individuals exposed to childhood trauma, with the long-term goal of identifying genetic modulators of brain structure that are informative for early prediction and treatment for a range of psychiatric disorders where childhood trauma is a major risk factor. We hypothesize that (1) childhood trauma will interact with specific genetic markers to produce structural brain alterations and adult psychopathology, (2) that unique genetic variants, in the context of genetic vulnerability to childhood trauma, will influence the onset of specific disorders (e.g. depression vs PTSD), as well as (3) the presentation of specific symptom constructs (e.g. sustained threat) across disorders. Finding disease-associated genetic variation that point to molecular mechanisms of pathogenesis has proven challenging due to the polygenicity of clinical phenotypes. Leveraging neuroimaging phenotypes may offer a more direct path than clinical phenotypes in identifying these elusive genetic markers and relevant neurobiological pathways. Ultimately, the promise of finding genetic contributors of any psychiatric disorder is in identifying the presence of new biologic pathways for which targeted interventions may be devised and deployed.

抽象的 关键的神经发育时期，童年时期的创伤和虐待是主要的危险因素 针对成人心理病理学。但是，并非所有暴露于童年创伤的儿童都会发展成人 心理病理学。预计与创伤相关病理风险的可变性部分是由遗传引起的 敏感性。最近已经确定了几种与儿童创伤相互作用以提高发生率的基因 成年后的焦虑和情绪障碍。通过检查可以更容易地检测到这种风险 由于具有更简单的基本遗传，诸如从MRI获得的脑测量之类的内型型 与推动总体风险的多种因素相比 心理病理学。了解合并大脑结构的分子遗传学因素 早期生活环境（心理创伤）并导致成人心理病理学，将需要大规模 利用大数据方法的协作努力。我们的目标是进行相关的GWA 接触儿童创伤的个体的结构性大脑测量，其长期目标是确定 大脑结构的遗传调节剂，对于早期预测和治疗的信息 童年创伤是主要危险因素的精神疾病。我们假设（1）儿童创伤 将与特定的遗传标记相互作用，以产生结构性的大脑改变和成人心理病理学， （2）在遗传脆弱性创伤的背景下，独特的遗传变异将影响 特定疾病的发作（例如抑郁症与PTSD）以及（3）特定症状的表现 跨疾病的构造（例如持续威胁）。查找与疾病相关的遗传变异指向 由于临床表型的多基因性，发病机理的分子机制已被证明具有挑战性。 利用神经影像型可能比临床表型提供更直接的路径 这些难以捉摸的遗传标记和相关的神经生物学途径。最终，找到遗传的希望 任何精神障碍的贡献者都在确定存在新的生物学途径的存在方面 可以设计和部署目标干预措施。