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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

基本信息

批准号：
10538610
负责人：
KENNETH SEEDMAN KENDLER
金额：
$ 58.12万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
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/10538610
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 Genomics Genotype Goals Health Heterogeneity 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 burden of illness cohort comorbidity design family genetics family structure gene environment interaction genetic architecture genetic epidemiology genetic resource genetic risk factor genome-wide improved microbiome offspring polygenic risk score population based programs prospective psychogenetics sex time use transmission process

项目摘要

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.

生命线队列中内化障碍病因学的综合方法