Neuroimaging Genetics of PTSD

PTSD 的神经影像遗传学

• 批准号: 8636651
• 负责人: MARK W MILLER
• 金额: $ 19.64万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636651
• 关键词: Affect; Attention; Boston; Brain; Brain region; Brain scan; Candidate Disease Gene; Caucasians; Caucasoid Race; Center for Translational Science Activities; Data; Development; Diagnostic; Dimensions; Disease; Distress; Emotions; Event; Fright; Future; Gene Chips; Genes; Genetic; Genetic Risk; Genomics; Genotype; Glucocorticoids; Healthcare Systems; Heritability; Individual; Individual Differences; Inflammation; Light; Location; Longevity; Magnetic Resonance Imaging; Measures; Memory; Mental Health; Military Personnel; Molecular Genetics; Natural Disasters; Nerve Degeneration; Neurons; Orphan; Oxidative Stress; Personal Communication; Pharmaceutical Preparations; Play; Population; Post-Traumatic Stress Disorders; Prevalence; Process; Psychopathology; Publishing; Recording of previous events; Regulation; Research; Research Personnel; Resolution; Risk; Role; Serotonin; Severities; Survivors; Symptoms; System; Terrorism; Testing; Thick; Trauma; Traumatic Brain Injury; Tretinoin; Twin Studies; Variant; Veterans; Violence; War; base; brain cell; brain morphology; cell injury; combat; density; design; disorder risk; gene function; genetic association; genetic variant; genome wide association study; interest; neural circuit; neuroimaging; public health priorities; public health relevance; receptor; relating to nervous system; resilience; response; risk variant; stress disorder; white matter

DESCRIPTION (provided by applicant): With terrorism, natural disasters, mass shootings, war and other forms of horror and violence on the rise across the globe, understanding the mental health consequences of these events, and treating survivors, has become a major public health priority. Posttraumatic stress disorder (PTSD) is the most common psychiatric consequence for survivors of such trauma and a serious and potentially disabling condition that affects 8-10% of individuals in the U.S. population at some point during their lifetimes (Kessler et al., 2012; Kessler et al., 1995). In those exposed to intense and repeated trauma, such as military combat, lifetime prevalence is considerably higher (i.e., closer to 20%). Twin studies have shown that a substantial proportion of variation in PTSD risk is attributable to hereditable factors leading investigators to begin to explore the molecular genetic basis of these effects. Unfortunately, results of genetic association studies conducted to date have been inconsistent and the heritability of PTSD remains largely unexplained. Recently, however, our research group published the first genome-wide association study (GWAS) of PTSD which implicated the Retinoic Acid Orphan Receptor Alpha gene (RORA) as a significant risk locus for the development of PTSD after trauma exposure (Logue et al., 2012). The primary finding from that study was subsequently replicated by an independent research group (Amstadter et al., 2013). We believe that the basis for RORA's association with PTSD lies in its role in protecting neurons from the effects of oxidative stress (OXS) and inflammation (INF). Specifically, we hypothesize that individuals who carry the RORA risk variant(s) have a reduced capacity to mount a neuroprotective response to the OXS and INF associated with PTSD. As a result, they are more likely to incur damage to regions of the brain involved in emotion, memory, attention, and other psychiatrically-relevant processes where the loss of neural integrity alters brain function and yields symptoms of the disorder. The primary aim of this study is to test this and related hypotheses using data from the Translational Research Center for Traumatic Brain Injury and Stress Disorders at VA Boston Healthcare System (TRACTS). Specifically, we propose to study the intersection of RORA genotype, other OXS and INF genes, PTSD and other psychopathology, and structural brain parameters using existing genomic data from a high-density gene chip and high resolution structural magnetic resonance imaging (MRI) brain scans from 190 Caucasian OEF/OIF veterans. We will also explore associations between other aspects of psychiatric illness and abnormalities in brain morphology and examine effects of mild Traumatic Brain Injury (mTBI) on these parameters. Evidence in support of our primary hypotheses could pave the way towards the development of medications designed to enhance protective RORA and OXS and INF gene function-and in doing so promote neural resilience in individuals with genetic risk variants.

描述（由申请人提供）：随着恐怖主义，自然灾害，大规模枪击事件，战争以及其他形式的恐怖和暴力，全球崛起，了解这些事件的心理健康后果以及对待幸存者的心理健康后果已成为主要的公共卫生优先事项。创伤后应激障碍（PTSD）是这种创伤的幸存者和严重且潜在的残疾疾病的最常见的精神病结果，在其一生中的某个时候影响了美国人口中8-10％的个人（Kessler等，2012; Kessler等人，2012; Kessler等人，1995年）。在暴露于强烈和反复创伤的人中，例如军事战斗，终生患病率要高得多（即接近20％）。双胞胎研究表明，PTSD风险的很大一部分归因于可遗传性的因素，导致研究人员开始探索这些作用的分子遗传基础。不幸的是，迄今为止进行的遗传关联研究结果并不一致，PTSD的遗传力仍然无法解释。然而，最近，我们的研究小组发表了PTSD的首个全基因组关联研究（GWAS），该研究涉及视黄酸孤儿受体α基因（RORA）是创伤后创伤后PTSD发展的重要风险基因座（Logue等人，2012年）。该研究的主要发现随后由一个独立的研究小组复制（Amstadter等，2013）。我们认为，Rora与PTSD相关的基础在于其在保护神经元免受氧化应激（OX）和炎症（INF）影响的作用。具体而言，我们假设携带RORA风险变体的个体具有对与PTSD相关的OX和INF的神经保护反应的能力降低。结果，它们更有可能会损害与情绪，记忆，注意力和其他与精神病相关的过程中涉及的大脑区域的损害，在这些过程中，神经完整性的丧失会改变大脑功能并产生疾病的症状。这项研究的主要目的是使用来自VA波士顿医疗系统（Tracts）转化研究中心的脑损伤和应激障碍研究中心的数据来检验和相关的假设。具体而言，我们建议使用现有的基因组基因芯片和高分辨率结构性磁共振成像（MRI）从190 Cacucasian OEF/OEF/OIF Veterans扫描的现有基因组数据研究RORA基因型，其他OX和INF基因，PTSD和其他心理病理学以及结构性大脑参数的相交。我们还将探索精神病的其他方面与脑形态异常之间的关联，并检查轻度创伤性脑损伤（MTBI）对这些参数的影响。支持我们主要假设的证据可以为开发旨在增强保护性RORA和OXS和INF基因功能的药物的发展铺平道路，并在此过程中促进具有遗传风险变异型患者的神经弹性。