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 内化障碍（ID）占全球疾病负担的很大比例， 共病并共享共同的病因途径。然而，在理解因果关系方面的进展 ID的底层机制一直很慢。本项目的总体目标是阐明病因， 五种主要内在化障碍（抑郁症[MD]，心境恶劣[DYS]， 广泛性焦虑症[GAD]和惊恐障碍[PD]，社交恐惧症[SPH]在生命线中， 荷兰东北部一项前瞻性基于人群的队列研究，随访167，729例成人受试者 每五年进行一次精神和一般医疗健康评估。生命线包括高 关于多代人的表型、环境、基因型和微生物组的质量数据 家庭成员和详细的评估，以及三大功能障碍 (FDs)（慢性疲劳综合征[CFS]，纤维肌痛[FM]和肠易激综合征[IBS]）， 与身份证高度共病这些数据的丰富性使得可以对疾病进行深入分析 机制等我们将建立多变量模型，包括表型，环境，家族， 分子遗传水平，以了解哪些机制是共享的，而不是特定的， 五个身份证和三个关联的身份证为了实现这些目标，我们提出了三个具体目标。在我们的第一个目标中，我们 将调查，利用一系列的因果推理和多元方法，病因关系 在ID之间以及ID和FD之间，利用Lifelines丰富的纵向和家族结构。 我们的第二个目标将是使用先进的遗传流行病学和分子遗传学方法应用 家族结构和全基因组SNP数据，以阐明ID的共同和独特风险因素 以及ID和FD之间的关系。我们将重新审视我们的疾病之间的因果关系， 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， 遗传和环境风险因素对ID和FD发展的相互作用。这将 包括研究遗传教养的影响。我们将再次使用免费的方法， 利用遗传流行病学和 分子遗传学为了进行这项跨学科的研究，我们在过去的5年里， 多年来，来自弗吉尼亚州精神病和行为遗传学研究所的一个广泛的合作团队， VCU和格罗宁根大学医学中心的精神病学和遗传学系， 荷兰.

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.