An Integrative Approach to the Etiology of Internalizing Disorders in the Lifelines Cohort

生命线队列中内化障碍病因学的综合方法

• 批准号: 10362893
• 负责人: KENNETH SEEDMAN KENDLER
• 金额: $ 62.6万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362893
• 关键词: Academic Medical Centers; Adult; Age; Behavioral Genetics; Blood; Brain; Chronic Fatigue Syndrome; Cohort Analysis; Data; Development; Disease; Dysthymic Disorder; Environment; Environmental Risk Factor; Epidemiologic Methods; Epidemiology; Equation; Etiology; Factor Analysis; Family; Family member; Fibromyalgia; Functional disorder; Gene Expression; Generalized Anxiety Disorder; Generations; Genes; Genetic; Genetic Risk; Genomics; Genotype; Goals; Health; Heterogeneity; Institutes; Irritable Bowel Syndrome; Joints; Major Depressive Disorder; Measures; Medical; Mendelian randomization; Mental disorders; Methods; Modeling; Molecular Genetics; Netherlands; Panic Disorder; Parents; Pathway interactions; Pattern; Phenotype; Principal Investigator; Psychiatry; Public Health; Quantitative Trait Loci; Recording of previous events; Research; Risk; Risk Factors; Siblings; Single Nucleotide Polymorphism; Social Phobia; Statistical Methods; Structure; Symptoms; Typology; Virginia; Whole Blood; base; burden of illness; cohort; comorbidity; design; family genetics; family structure; gene environment interaction; genetic architecture; genetic epidemiology; genetic resource; genome-wide; improved; microbiome; offspring; polygenic risk score; population based; programs; prospective; psychogenetics; sex; time use; transmission process

An Integrative Approach to the Etiology of Internalizing Disorders in the Lifelines Cohort Internalizing Disorders (IDs) account for a substantial proportion of global disease burden, are highly comorbid and share common etiologic pathways. However, progress in understanding the causal mechanisms underlying IDs has been slow. The overall aim of this project is to clarify the etiology, course and comorbidities of five major internalizing disorders (Major Depression [MD], Dysthymia [DYS], Generalized Anxiety disorder [GAD] and Panic Disorder [PD], Social Phobia [SPH] in Lifelines, a prospective population-based cohort in North-Eastern Netherlands following 167,729 adult subjects with assessments of psychiatric and general medical health every five years. Lifelines includes high quality data on the phenotypes, environments, genotypes, and microbiome of multiple generations of family members and detailed assessments of the IDs as well as the three major functional disorders (FDs) (Chronic Fatigue Syndrome [CFS], Fibromyalgia [FM] and Irritable Bowel Syndrome [IBS]) which are highly comorbid with IDs. The richness of this data allows for an in-depth analysis of disease mechanisms. We will build multivariate models that include the phenotypic, environmental, familial, and molecular genetic levels to understand which of the mechanisms are shared amongst versus specific to the 5 IDs and 3 associated FDs. To meet these goals, we propose three specific aims. In our first aim, we will investigate, utilizing a range of causal inference and multivariate methods, the etiologic relations between IDs and between IDs and FDs, leveraging the rich longitudinal and family structure of Lifelines. Our second aim will be to use advanced genetic epidemiologic and molecular genetic methods applied to both family structure and genome wide SNP data to clarify the shared and unique risk factors for IDs and between ID and FDs. We will re-look at causal inter-relationships among our disorders using Mendelian Randomization. Building on aims 1 and 2, our third aim will investigate the joint action and interaction of genetic and environmental risk factors on the development(s) of IDs and FDs. This will include examining the effects of genetic nurture. We will again be using complimentary methods to examine gene x environment interactions utilizing methods from both genetic epidemiology and molecular genetics. To conduct this cross-disciplinary research, we have assembled, over the last 5 years, a broad collaborative team from the Virginia Institute for Psychiatric and Behavioral Genetics at VCU and the departments of Psychiatry and Genetics at the University Medical Center Groningen, Netherlands.

一种综合方法，用于内部化疾病的病因 内部化疾病（IDS）占全球疾病负担的很大一部分，高度 合并并共享常见的病因途径。但是，了解因果关系的进展 mechanisms underlying IDs has been slow. The overall aim of this project is to clarify the etiology, course and comorbidities of five major internalizing disorders (Major Depression [MD], Dysthymia [DYS], 普遍的焦虑症[GAD]和恐慌症[PD]，寿命中的社会恐惧症[SPH] 167,729名成人受试者之后，荷兰东北部的前瞻性人群队列 每五年对精神病和一般医疗健康的评估。寿命包括高 关于表型，环境，基因型和微生物组的质量数据 家庭成员和ID的详细评估以及三种主要功能障碍 （FDS）（慢性疲劳综合征[CFS]，纤维肌痛[FM]和肠易激综合症[IBS]） 与ID高度合并。 The richness of this data allows for an in-depth analysis of disease 机制。我们将构建包括表型，环境，家族和家族的多元模型 分子遗传水平以了解哪种机制在 5个ID和3个相关的FD。为了实现这些目标，我们提出了三个具体目标。在我们的第一个目标中，我们 将利用一系列因果推理和多元方法研究病因学关系 在ID和ID和FD之间，利用了寿命丰富的纵向和家庭结构。 Our second aim will be to use advanced genetic epidemiologic and molecular genetic methods applied to both family structure and genome wide SNP data to clarify the shared and unique risk factors for IDs and between ID and FDs. We will re-look at causal inter-relationships among our disorders using 孟德尔随机化。在目标1和2的基础上，我们的第三个目标将调查联合行动，并 interaction of genetic and environmental risk factors on the development(s) of IDs and FDs.这会 包括检查遗传培育的影响。 We will again be using complimentary methods to examine gene x environment interactions utilizing methods from both genetic epidemiology and molecular genetics. To conduct this cross-disciplinary research, we have assembled, over the last 5 years, a broad collaborative team from the Virginia Institute for Psychiatric and Behavioral Genetics at VCU以及Groningen大学医学中心的精神病学和遗传学部门 荷兰。