Gene-Environment Interplay in the Comorbidity of PTSD and Disordered Eating

个人描述(申请人提供)：我是波士顿大学医学院精神病学助理教授，弗吉尼亚州波士顿医疗系统国家创伤后应激障碍中心的临床研究心理学家。我的K01申请中提出的培训计划，即遗传和环境因素在创伤后应激障碍和饮食障碍共病中的相互作用，将极大地加强我在心理学、行为遗传学和饮食障碍方面的博士前培训。为了实现我的长期目标，即对创伤后应激障碍、饮食和体重障碍以及相关的精神疾病进行基因知情调查，我需要接受高级双胞胎建模方法以及分子和遗传流行病学研究方面的培训。设计精神病学遗传学五年培训计划的一个特别挑战是，这个领域变化很快。因此，这个培训计划的首要目标是，除了学习具体的技术之外，还要建立一个坚实的基础，使我首先能够跟上精神病学遗传学领域的不断变化的目标，然后开始设计研究，克服现有研究的一些限制。我提出了一个全面的培训计划，内容涉及创伤后应激障碍的病因学和心理生物学、分子遗传学和遗传流行病学、高级双胞胎模型、遗传和环境因素网络模型以及表观遗传学。这一培训将为我提供强大的知识基础，以产生关于精神遗传机制的假说。为了获得这个职业发展奖，我精心挑选了一个由创伤后应激障碍、饮食失调和遗传学领域的顶尖研究人员组成的多学科导师团队。这种指导，加上我的机构提供的资源，将确保我获得所有必要的支持，以实现我的培训和研究目标。BUSM和VA Boston都致力于我的职业发展和受保护的研究时间，如所附信件所述。我将以独特的方式访问这两个杰出机构的设施、资源和合作，包括办公空间， 图书馆，以及研究设备和技术。我的首要职业目标是将最新和最好的方法应用于创伤后应激障碍和饮食失调的遗传流行病学研究。这项应用将调查遗传和环境因素在病因和共病中的相互作用。创伤后应激障碍是一种令人衰弱的疾病，在美国，10.4%的女性和5%的男性会在一生中受到影响，它与其他医学和精神诊断高度共存。在国家共病调查-复制研究中，40%的终生BN女性和26%的终生卧床女性符合终生创伤后应激障碍的标准，66%的BN男性和24%的卧床男性符合终生创伤后应激障碍的标准。有几种心理社会和遗传机制可能解释了创伤后应激障碍-DE共病。创伤与暴饮暴食和排泄行为有关，它可能会直接影响一个人的身体形象。此外，创伤后应激障碍和痴呆有共同的相关特征，包括述情障碍、情绪失调和冲动。De行为也可以作为一种自我治疗创伤后应激障碍症状和相关负面情绪的手段。此外，创伤后应激障碍和痴呆可能具有共同的遗传易感性。然而，仍然需要研究PTSD-DE共病的遗传机制，以及这些机制中哪些是疾病中常见的，哪些是PTSD和DE病因所独有的。这项拟议的研究将检验三个主要模型，以确定PTSD和DE之间的共生关系的性质：1)创伤暴露引发PTSD和DE的遗传易感性，2)PTSD和DE具有共同的遗传和心理社会脆弱性，以及3)产前母亲应激暴露导致后代表观遗传变化和DE。将使用三组数据来解决这三个目标：1)越南时代双胞胎老龄化研究(VETSA)的男性参与者，2)护士健康研究II(NHS II)的女性，以及3)雅芳父母和孩子纵向研究(ALSPAC)的男性和女性后代。研究1将测试一系列双胞胎模型，以调查PTSD和DE的协方差在多大程度上是由共同的遗传和环境影响造成的，并估计基因-环境交互作用的影响。研究2将评估与创伤后应激障碍和精神障碍相关的遗传和心理社会变量的网络模型。研究3将调查母亲产前应激暴露是否与后代全基因组DNA甲基化变化和DE有关。此外，这项研究将调查这些关联是否适用于物质使用的病因学和抑郁症状学，以及DE。这项拟议的工作具有创新性，因为它使用了几种尖端方法来研究遗传和环境因素在PTSD和DE的病因和共病中的相互作用。预计这些疾病将具有几个关键的遗传和心理社会脆弱性。此外，预计胎儿期应激暴露将与子代青春期痴呆相关，这种关系将通过DNA甲基化变化来调节。这些发现将为未来的基因研究以及治疗和预防工作提供基础。此外，预计这些结果将使首席调查员在授权期的第四年前提交一份具有竞争力的R01。

DESCRIPTION (provided by applicant): I am an Assistant Professor of Psychiatry at Boston University School of Medicine (BUSM) and a Clinical Research Psychologist in the National Center for Posttraumatic Stress Disorder (PTSD) at VA Boston Healthcare System. The proposed training plan of my K01 application, The Interplay of Genetic and Environmental Factors in the Comorbidity of PTSD and Disordered Eating, would greatly enhance my predoctoral training in psychology, behavioral genetics, and eating disorders. In order to accomplish my long- term goal of conducting genetically informed investigations of PTSD, eating and weight disorders, and related psychiatric comorbidity, I require training in advanced twin modeling methodology as well as molecular and genetic epidemiology research. A particular challenge of designing a 5-year training plan in psychiatric genetics is that the field changes quite rapidly. Thus, an overarching goal of this training plan, above and beyond learning specific techniques, is to build a solid foundation that will allow me to first keep up wih the moving target that is the field of psychiatric genetics and second to begin to design studies that will overcome some of the limitations of extant research. I propose a comprehensive training program in the etiology and psychobiology of PTSD, molecular genetics and genetic epidemiology, advanced twin modeling, network models of genetic and environmental factors, and epigenetics. This training will provide me with a strong knowledge base from which to generate hypotheses about psychiatric genetic mechanisms. For this career development award, I have carefully chosen a multidisciplinary mentorship team of top researchers in the fields of PTSD, eating disorders, and genetics. This mentorship, along with resources available at my institutions, will ensure that I have all the support necessary to meet my training and research goals. Both BUSM and VA Boston are committed to my career development and protected research time, as described in the attached letters. I will have unique access to facilities, resources, and collaborations at both outstanding institutions, including office space, libraries, and research equipment and technology. My overarching career goal is to apply the latest and best methods to the study of the genetic epidemiology of PTSD and disordered eating. This application will investigate the interplay of genetic and environmental factors in ther etiology and comorbidity. PTSD, a debilitating condition that affects 10.4% of women and 5% of men in the United States during their lifetimes, is highly comorbid with other medical and psychiatric diagnoses. In the National Comorbidity Survey-Replication study, 40% of women with lifetime BN and 26% of women with lifetime BED met criteria for lifetime PTSD, as did 66% of men with BN and 24% of men with BED. There are several psychosocial and genetic mechanisms that may account for PTSD - DE comorbidity. Trauma, which has been associated with bingeing and purging behaviors, may directly impact one's body image. In addition, PTSD and DE share common associated features, including alexithymia, emotion dysregulation, and impulsivity. DE behaviors also may serve as a means to self-medicate the symptoms of PTSD and associated negative affect. In addition, PTSD and DE likely share a common genetic vulnerability. However, there remains a need for investigation of genetic mechanisms of PTSD - DE comorbidity, as well as which of these mechanisms are common across disorders and those that are unique to the etiology of PTSD and DE. The proposed research will test three main models determine the nature of the comorbid relationship between PTSD and DE: 1) genetic vulnerability to PTSD and DE is triggered by trauma exposure, 2) PTSD and DE have common genetic and psychosocial vulnerabilities, and 3) prenatal maternal stress exposure leads to offspring epigenetic changes and DE. Three datasets will be used to address these three aims: 1) male participants in the Vietnam Era Twin Study of Aging (VETSA), 2) women from the Nurses Health Study II (NHS II), and 3) male and female offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC). Study 1 will test a series of twin models to investigate the extent to which the covariance of PTSD and DE is due to shared genetic and environmental influences and estimate the impact of gene-environment interaction. Study 2 will estimate a network model of genetic and psychosocial variables associated with PTSD and DE. Study 3 will investigate whether maternal prenatal stress exposure is associated with offspring genome-wide DNA methylation changes and DE. In addition, this study will investigate whether these associations apply to the etiology of substance use and depressive symptomatology, as well as DE. The proposed work is innovative in that it uses several cutting-edge methodologies to investigate the interplay of genetic and environmental factors in the etiology and comorbidity of PTSD and DE. It is expected that these disorders will share several key genetic and psychosocial vulnerabilities. Further, it is expected that exposure to prenatal stress will be associated with offspring adolescent DE and that this relation will be mediated by DNA methylation changes. Findings will provide a foundation for future genetic studies, as well as treatment and prevention efforts. Further, these outcomes are expected to position the Principal Investigator to submit a competitive R01 by the fourth year of the award period.