Neuroimaging Genetics of PTSD

描述（由申请人提供）：随着恐怖主义、自然灾害、大规模枪击、战争和其他形式的恐怖和暴力在全球范围内的上升，了解这些事件对心理健康的影响，并治疗幸存者，已成为一项主要的公共卫生优先事项。创伤后应激障碍（PTSD）是此类创伤幸存者最常见的精神后果，是一种严重且潜在致残的疾病，在美国人口中有8-10%的人在其一生的某个阶段受到影响（Kessler et al., 2012; Kessler et al., 1995）。在暴露于强烈和反复创伤（如军事战斗）的人中，终生患病率要高得多（即接近20%）。双胞胎研究表明，创伤后应激障碍风险的很大一部分变化可归因于遗传因素，这使得研究人员开始探索这些影响的分子遗传基础。不幸的是，迄今为止进行的遗传关联研究的结果并不一致，创伤后应激障碍的遗传性在很大程度上仍然无法解释。然而，最近，我们的研究小组发表了首个创伤后应激障碍的全基因组关联研究（GWAS），该研究表明视黄酸孤儿受体α基因（RORA）是创伤暴露后PTSD发展的重要风险位点（Logue et al., 2012）。该研究的主要发现随后被一个独立研究小组复制（Amstadter et al., 2013）。我们认为RORA与PTSD相关的基础在于其保护神经元免受氧化应激（OXS）和炎症（INF）的影响。具体来说，我们假设携带RORA风险变异的个体对与PTSD相关的OXS和INF产生神经保护反应的能力降低。因此，他们更有可能对大脑中涉及情感、记忆、注意力和其他精神相关过程的区域造成损害，在这些区域，神经完整性的丧失改变了大脑功能，并产生了这种疾病的症状。本研究的主要目的是利用VA波士顿医疗保健系统（TRACTS）创伤性脑损伤和应激障碍转化研究中心的数据来验证这一假设和相关假设。具体而言，我们建议利用高密度基因芯片和高分辨率结构磁共振成像（MRI）脑部扫描的现有基因组数据，研究RORA基因型、其他OXS和INF基因、PTSD和其他精神病理以及大脑结构参数的交叉。我们还将探讨精神疾病的其他方面与脑形态异常之间的联系，并检查轻度创伤性脑损伤（mTBI）对这些参数的影响。支持我们的主要假设的证据可以为开发旨在增强RORA、OXS和INF基因保护功能的药物铺平道路，从而促进具有遗传风险变异个体的神经恢复能力。

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.