Gene x Environment Effects on PTSD

描述（由申请人提供）： 持久自由行动、伊拉克自由行动和新黎明行动（OEF/OIF/OND）退伍军人所特有的部署数量和时间的增加使他们处于创伤后应激障碍发展的风险之中。虽然战斗暴露，持续的压力，缺乏社会支持和童年逆境对创伤后应激障碍的影响是相对确定的，但退伍军人对这些压力源的反应存在很大的差异，这可能是由于遗传易感性的差异。此外，导致创伤后应激障碍发展的特定基因在很大程度上仍然未知，这些基因可能相互作用的方式以及环境因素产生和维持这种衰弱状况的方式也是如此。缺乏这方面的知识是一个重要的问题，因为它限制了我们在退伍军人中预防和治疗PTSD的能力。 拟议研究的长期目标是确定基因相互作用的方式以及退伍军人中产生和维持精神疾病的环境。该研究将有助于这一目标，通过使用遗传建模程序（包括单倍型分析），以检查两个有前途的候选基因-血清素转运蛋白基因（SLC 6A 4）和脑源性神经营养因子（BDNF）基因对PTSD的影响。虽然以前对平民的研究表明研究这些基因与PTSD的重要性，但SLC 6A 4，BDNF和环境压力源（如战斗暴露）之间的相互作用尚未在退伍军人中进行过测试。这项研究的具体目的是：（1）检查战斗暴露、持续压力、社会支持和童年逆境对PTSD的直接影响;（2）检查SLC 6A 4和BDNF对PTSD的直接影响;（3）检查战斗暴露、持续压力、缺乏社会支持和童年逆境对PTSD的影响是否受到SLC 6A 4和BDNF变异的调节。为了实现拟议的目标，将招募300名男性OEF/OIF/OND退伍军人样本，有和没有PTSD。将收集标准化的临床访谈和自我报告数据，以评估退伍军人的诊断状态和症状严重程度。战斗暴露，紧张的生活事件，社会支持和童年逆境将通过自我报告进行评估。将采集血液样本，以便参与者可以进行SLC 6A 4和BDNF变异的基因分型。还将对一组24个短串联重复序列基因座进行基因分型，以评估和控制潜在的人群分层。遗传建模程序和潜在调节结构方程将被用来测试的假设。 拟议的CDA将为Kimbrel博士提供指导研究时间，以便他能够实现成为独立VA科学家的目标。Kimbrel博士对研究创伤后应激障碍的病因特别感兴趣，这与退伍军人和VA研究使命具有高度相关性。拟议中的CDA将为他提供精神病学遗传学，统计遗传学，PTSD研究方法，伦理学和研究管理方面的高级培训。反过来，这种培训将使他能够开发和实施G x E和G x G研究的纲领性路线，重点是退伍军人中创伤后应激障碍的病因。

DESCRIPTION (provided by applicant): STATEMENT OF THE RESEARCH PROBLEM The increased number and length of deployments unique to Operation Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND) Veterans places them at risk for the development of PTSD. While the impact of combat exposure, ongoing stress, lack of social support, and childhood adversity on PTSD is relatively well- established, there is substantial variability in Veterans' response to these stressors that may be due to differences in genetic susceptibility. Moreover, the specific genes that contribute to the development of PTSD remain largely unknown, as does the manner in which these genes might interact with each other and environmental factors to produce and maintain this debilitating condition. Lack of such knowledge is an important problem because it limits our ability to prevent and treat PTSD among returning Veterans. RESEARCH OBJECTIVES The long range goal of the proposed research is to identify the manner in which genes interact with each other and the environment to produce and maintain psychiatric disorders among Veterans. The proposed study will contribute to this goal by using genetic modeling procedures (including haplotype analyses) to examine the effects of two promising candidate genes-the serotonin transporter gene (SLC6A4) and the brain-derived neurotrophic factor (BDNF) gene on PTSD. While previous research with civilians suggests the importance of studying these genes in relation to PTSD, the interactions among SLC6A4, BDNF, and environmental stressors like combat exposure have not been tested among Veterans. The specific aims of the proposed research are to: (1) Examine the direct effects of combat exposure, ongoing stress, social support, and childhood adversity on PTSD; (2) Examine the direct effects of SLC6A4 and BDNF on PTSD; and (3) Examine whether the effects of combat exposure, ongoing stress, lack of social support, and childhood adversity on PTSD are moderated by SLC6A4 and BDNF variation. To achieve the proposed objectives, a sample of 300 male OEF/OIF/OND Veterans with and without PTSD will be recruited. Standardized clinical interview and self-report data will be collected to assess Veterans' diagnostic status and symptom severity. Combat exposure, stressful life events, social support, and childhood adversity will be assessed via self-report. Blood samples will be collected so that participants can be genotyped for SLC6A4 and BDNF variation. A panel of 24 short tandem repeat loci will also be genotyped to assess and control for potential population stratification. Genetic modeling procedures and latent moderated structural equations will be used to test the hypotheses. TRAINING OBJECTIVES The proposed CDA will provide Dr. Kimbrel with mentored research time so that he can achieve his goal of becoming an independent VA Scientist. Dr. Kimbrel is particularly interested in studying the etiology of PTSD, which is of high relevance to Veterans and the VA research mission. The proposed CDA will provide him with advanced training in psychiatric genetics, statistical genetics, PTSD research methods, ethics, and research administration. In turn, this training will enable him to develop and implement a programmatic line of G x E and G x G research focused on the etiology of PTSD among Veterans.