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

描述（由申请人提供）：我是波士顿大学医学院（BUSM）精神病学助理教授，也是VA波士顿医疗系统国家创伤后应激障碍（PTSD）中心的临床研究心理学家。我在K01申请中提出的“The Interplay of Genetic and Environmental Factors in Comorbidity of PTSD and disorder Eating”的训练计划，将极大地加强我在心理学、行为遗传学和饮食失调方面的博士前训练。为了完成我的长期目标，对创伤后应激障碍、饮食和体重失调以及相关的精神共病进行遗传知情调查，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5年培训计划的一个特别挑战是，这个领域变化很快。因此，除了学习特定的技术之外，这个培训计划的首要目标是建立一个坚实的基础，使我能够首先跟上精神病学遗传学领域的移动目标，其次开始设计研究，克服现有研究的一些局限性。我建议在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方面开展全面的培训计划。这次培训将为我提供一个强大的知识基础，从中产生关于精神病学遗传机制的假设。为了这个职业发展奖，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指导团队。这种指导，加上我所在机构的资源，将确保我得到所有必要的支持，以实现我的培训和研究目标。如所附信件所述，BUSM和VA Boston都致力于我的职业发展和保护研究时间。我将有独特的机会使用这两所优秀机构的设施、资源和合作，包括办公空间，

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.