Imaging-Genetics of PTSD in OEF/OIF Veterans

描述(由申请人提供)： 创伤后应激障碍(PTSD)影响了25%暴露于战斗创伤的人。疾病对环境因素反应的异质性可归因于遗传差异。不同的人可能会经历相同的创伤暴露，并患上或不患上创伤后应激障碍。这与遗传脆弱性可能增加这种疾病风险的假设是一致的。成像遗传学利用神经成像和遗传研究的优势，在遗传背景的背景下可视化大脑激活模式。影像作为一种中间表型可以阐明基因和疾病表型之间的功能联系。鉴于遗传学和环境在大脑功能中的重要性以及神经成像在揭示大脑功能障碍方面的作用，将遗传学与脑成像相结合具有明显的优势：(1)可以在神经成像数据中揭示感兴趣基因的功能，这是一种与许多疾病相关的中间表型；(2)通过控制遗传背景，成像研究中不必要的变异可以减少；(3)神经成像可以识别与易感基因关系更密切的疾病的维度，而不是目前的临床分类；(4)基因发现或与疾病相关的新基因的鉴定，这些基因是传统候选基因方法无法发现的。在这项提案中，我们计划利用大西洋中部精神疾病教育和临床中心的大量投资，收购OEF/OIF退伍军人的大型数据库，以使用神经成像表型来研究基因对PTSD发展的影响。这项建议反映了MIRECC临床医生、神经影像科学家和精神病学遗传学家的合作。总的来说，我们的三个具体目标是整合脑成像和人类基因分型方面的先进方法，以识别与创伤后应激障碍相关的新基因，并了解这些基因在大脑功能中所起的作用。我们的第一个目标是在工作记忆任务和情绪处理任务中对患有创伤后应激障碍的OEF/OIF退伍军人(n=80)和创伤暴露对照组(n=80)进行功能磁共振研究，以确定不同激活的大脑区域。我们的第二个目标是基于工作记忆和情绪处理的生物学合理性来测试五个候选基因的目标清单。我们的第三个目标是分析Aim 2的基因信息和Aim 1的脑激活信息，以研究基因、脑激活和额顶背侧区和腹侧额边缘区PTSD严重程度之间的交互作用。通过这种方式，成像遗传学方法有望帮助识别与创伤后应激障碍相关的基因。 公共卫生相关性： 创伤后应激障碍(PTSD)对OEF/OIF退伍军人的心理健康、社会和职业影响在公共话语的各个层面都受到了极大的关注，特别是在心理健康政策和提供方面。创伤后应激障碍影响了25%遭受战斗创伤的人。这表明，对创伤暴露的反应差异可以归因于遗传差异。了解基因对创伤后应激障碍的脑功能、行为和疾病表现的影响对于发展有效的治疗和治疗至关重要。

DESCRIPTION (provided by applicant): Posttraumatic stress disorder (PTSD) affects 25% of those exposed to combat trauma. The heterogeneity in illness response to environmental factors can be attributed to genetic differences. Different individuals can experience the same trauma exposure and develop, or not develop, PTSD. This is consistent with the hypothesis that genetic vulnerability may confer risk for the disorder. Imaging genetics leverages the strengths of both neuroimaging and genetic studies, visualizing the brain activation patterns in the context of genetic background. Imaging as an intermediate phenotype can clarify the functional link between gene and disease phenotype. Given the known importance of both genetics and environment in brain function, and the role of neuroimaging in revealing brain dysfunction, the synergy of integrating genetics with brain imaging carries clear advantages: (i) the function of the genes of interest can be revealed in neuroimaging data, an intermediate phenotype which has relevance to many diseases; (ii) the unwanted variation in imaging studies can be reduced through controlling for genetic background; (iii) neuroimaging may identify dimensions of disease that are more closely related to susceptibility genes than are current clinical categorizations; (iv) gene discovery or the identification of new genes related to illness that would not be discovered by traditional candidate gene approaches. In this proposal, we plan to leverage the substantial investment of the Mid-Atlantic Mental Illness Education and Clinical Center in acquiring a large database of OEF/OIF veterans to investigate the influence of genes on the development of PTSD using neuroimaging phenotypes. This proposal reflects a collaboration of MIRECC clinicians, neuroimaging scientists, and psychiatric geneticists. Broadly, our three specific aims integrate advanced methods in brain imaging and human genotyping to identify new genes associated with PTSD and understand the role these genes play in brain function. Our first aim is to perform functional MRI studies on OEF/OIF veterans with PTSD (n=80) and trauma exposed controls (n=80) in a working memory task and emotion processing task to identify brain regions of differential activation. Our second aim is to assay a targeted list of five candidate genes based on biological plausibility in working memory and emotion processing. Our third aim is to analyze the genotype information from Aim 2 and brain activation information from Aim 1 to study the interaction of genotype, brain activation, and PTSD severity in dorsal frontoparietal regions and ventral frontolimbic regions. In this manner an imaging-genetics approach is expected to help identify genes associated with PTSD. PUBLIC HEALTH RELEVANCE: The mental health, social, and occupational impact of posttraumatic stress disorder (PTSD) on OEF/OIF veterans has received a great deal of attention at all levels of public discourse espically in mental health policy and delivery. PTSD affects 25% of those exposed to combat trauma. This suggests that differences in response to trauma exposure can be attributed to genetic differences. Understanding the effects of genes on brain function, behavior, and disease expression of PTSD are crucial to developing effective management and treatment.