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

生命线队列内在化障碍病因的综合研究 内在化疾病(ID)在全球疾病负担中占相当大的比例， 共病并分享共同的病因。然而，在理解原因方面的进展 支持入侵检测的机制一直进展缓慢。这个项目的总体目标是弄清病因， 五种主要内化障碍(重度抑郁[MD]、恶劣心境[DYS]、 广泛性焦虑症[GAD]和惊恐障碍[PD]，生活中的社交恐惧症[SPH]，a 荷兰东北部167,729名成年受试者的前瞻性人群队列研究 每五年评估一次精神和一般医学健康状况。生命线包括高 关于多个世代的表型、环境、基因型和微生物组的高质量数据 家庭成员和详细评估的IDS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]) 与身份证高度并存。这些数据的丰富性使得对疾病的深入分析成为可能 机械装置。我们将建立包括表型、环境、家族性和 分子遗传水平，以了解哪些机制是共同的，而不是特定于 5个ID和3个关联的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来调查病因之间的关系 在ID之间以及ID和FD之间，利用生命线丰富的纵向和家庭结构。 我们的第二个目标是使用先进的遗传流行病学和分子遗传学方法 获得家庭结构和全基因组SNP数据，以阐明共同和独特的IDs风险因素 以及ID和FDS之间的关系。我们将使用以下工具重新审视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和 遗传和环境风险因素在IDs和FDs发生中的交互作用(S)。这将是 包括检查基因培育的影响。我们将再次使用免费的方法来 利用遗传流行病学和遗传流行病学的方法研究基因与环境的相互作用 分子遗传学。为了进行这项跨学科的研究，我们在过去的5年里收集了 几年来，弗吉尼亚精神病学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.