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

创伤后应激障碍 (PTSD) 和饮食失调合并症中的基因-环境相互作用

• 批准号: 8459920
• 负责人: KAREN Suzanne MITCHELL
• 金额: $ 17.56万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459920
• 关键词: Accounting; Address; Adolescent; Affect; Aging; Alcohol or Other Drugs use; Animal Model; Anxiety; Asthma; Award; Behavioral Genetics; Binge eating disorder; Biological Factors; Body Image; Boston; Bulimia; Cause of Death; Child; Chronic stress; Clinical Research; Collaborations; Commit; Comorbidity; DNA Methylation; Data Set; Development; Disease; Eating; Eating Behavior; Eating Disorders; Emotions; Ensure; Environment; Environmental Risk Factor; Epidemiologic Studies; Epidemiologist; Epigenetic Process; Equipment; Etiology; Exposure to; Female; Foundations; Future; Genes; Genetic; Genetic Predisposition to Disease; Goals; Healthcare Systems; Human; Impulsivity; Individual; Institution; Investigation; K-Series Research Career Programs; Learning; Letters; Libraries; Longitudinal Studies; Mediating; Medical; Mental Depression; Mentorship; Metabolic syndrome; Methodology; Methods; Modeling; Molecular Epidemiology; Molecular Genetics; Nature; Nurses' Health Study; Obesity; Outcome; Overweight; Parents; Participant; Pathway interactions; Pattern; Phenotype; Play; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Prevalence; Prevention; Principal Investigator; Probability Samples; Psychiatric Diagnosis; Psychiatry; Psychologist; Psychology; Psychosocial Factor; Public Health; Recording of previous events; Research; Research Design; Research Personnel; Research Training; Resources; Risk; Role; Sampling; Series; Sex Characteristics; Solid; Specific qualifier value; Strategic Planning; Stress; Stroke; Substance Use Disorder; Surveys; Symptoms; Techniques; Technology; Testing; Time; Training; Training Programs; Trauma; Twin Multiple Birth; Twin Studies; United States; Universities; Vietnam; Weight; Woman; Work; binge type behavior; career; career development; depressive symptoms; design; gene environment interaction; genetic epidemiology; genome-wide; hypothalamic-pituitary-adrenal axis; innovation; insight; knowledge base; male; maternal stress; medical schools; meetings; multidisciplinary; network models; offspring; pre-doctoral; prenatal; prenatal stress; professor; psychobiology; psychogenetics; psychosocial; purging behavior; response

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.

描述（由申请人提供）：我是波士顿大学医学院 (BUSM) 的精神病学助理教授和 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。我的 K01 应用程序拟议的培训计划“遗传和环境因素在创伤后应激障碍和饮食失调共病中的相互作用”将极大地增强我在心理学、行为遗传学和饮食失调方面的博士前培训。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精神共病进行遗传学调查，我需要接受先进的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。设计精神遗传学五年培训计划的一个特殊挑战是该领域变化非常快。因此，除了学习特定技术之外，该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遗传学领域的移动目标，其次开始设计研究，以克服现有研究的一些局限性。我提出了一个关于创伤后应激障碍（PTSD）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、遗传和环境因素的网络模型以及表观遗传学的综合培训计划。这次培训将为我提供强大的知识基础，从而生成有关精神病遗传机制的假设。对于这个职业发展奖，我精心挑选了一支由创伤后应激障碍、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。这种指导以及我所在机构提供的资源将确保我获得实现我的培训和研究目标所需的所有支持。 BUSM 和 VA Boston 都致力于我的职业发展并保护研究时间，如所附信件中所述。我将有独特的机会获得这两个杰出机构的设施、资源和合作，包括办公空间、 图书馆、研究设备和技术。我的首要职业目标是应用最新、最好的方法来研究创伤后应激障碍和饮食失调的遗传流行病学。该应用程序将研究遗传和环境因素在病因和合并症中的相互作用。创伤后应激障碍 (PTSD) 是一种使人衰弱的疾病，影响着美国 10.4% 的女性和 5% 的男性一生，它与其他医学和精神疾病诊断高度共存。在全国合并症调查复制研究中，40% 患有终生 BN 的女性和 26% 患有终生 BED 的女性符合终生 PTSD 的标准，66% 患有 BN 的男性和 24% 患有 BED 的男性也符合终生 PTSD 的标准。有几种社会心理和遗传机制可以解释 PTSD - DE 合并症。与暴饮暴食和清除行为有关的创伤可能会直接影响一个人的身体形象。此外，PTSD 和 DE 具有共同的相关特征，包括述情障碍、情绪失调和冲动。 DE 行为也可以作为自我治疗 PTSD 症状和相关负面情绪的一种手段。此外，PTSD 和 DE 可能具有共同的遗传脆弱性。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跨疾病常见的，以及哪些是 PTSD 和 DE 病因学所独有的。拟议的研究将测试三个主要模型，以确定 PTSD 和 DE 之间共病关系的性质：1）创伤暴露引发了对 PTSD 和 DE 的遗传脆弱性，2）PTSD 和 DE 具有共同的遗传和心理社会脆弱性，3）产前母亲压力暴露导致后代表观遗传变化和 DE。将使用三个数据集来实现这三个目标：1）越南时代双胞胎衰老研究 (VETSA) 的男性参与者，2) 护士健康研究 II (NHS II) 的女性参与者，以及 3) 雅芳父母和儿童纵向研究 (ALSPAC) 的男性和女性后代。研究 1 将测试一系列双胞胎模型，以研究 PTSD 和 DE 的协方差在多大程度上归因于共同的遗传和环境影响，并估计基因-环境相互作用的影响。研究 2 将估计与 PTSD 和 DE 相关的遗传和社会心理变量的网络模型。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 相关。此外，本研究将调查这些关联是否适用于物质使用和抑郁症状以及 DE 的病因学。这项工作的创新之处在于它使用了几种前沿方法来研究遗传和环境因素在 PTSD 和 DE 的病因和合并症中的相互作用。预计这些疾病将具有几个关键的遗传和社会心理脆弱性。此外，预计暴露于产前应激将与后代青少年 DE 相关，并且这种关系将由 DNA 甲基化变化介导。研究结果将为未来的遗传学研究以及治疗和预防工作奠定基础。此外，这些结果预计将使首席研究员能够在奖励期的第四年提交有竞争力的 R01。