Family Study of Affective and Anxiety Spectrum Disorders

情感和焦虑谱系障碍的家庭研究

• 批准号: 10011358
• 负责人: kathleen r merikangas
• 金额: $ 232.07万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10011358
• 关键词: Adult; Affective; Age; Anxiety; Anxiety Disorders; Attention deficit hyperactivity disorder; Atypical depressive disorder; Australia; Autonomic nervous system; Biological; Biological Factors; Biological Markers; Bipolar Disorder; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Child; China; Circadian Rhythms; Clinical; Clinical assessments; Cognitive; Collaborations; Collection; Communities; Comorbidity; Computers; Copy Number Polymorphism; DNA; Data; Data Set; Development; Devices; Diagnostic; Diet; Disease; Disease remission; Disease susceptibility; Early Intervention; Ecological momentary assessment; Emotional; Enrollment; Etiology; Evaluation; Event; Evolution; Family; Family Study; Family member; Future; Genetic; Genotype; Goals; Headache; Heart Rate; Heritability; Holter Electrocardiography; Hormones; Incidence; Individual; Interview; Intramural Research Program; Laboratories; Lead; Life; Longevity; Magnetic Resonance Imaging; Major Depressive Disorder; Manic; Measures; Medical; Medical History; Mental Depression; Mental disorders; Metabolic; Methodological Studies; Methodology; Methods; Migraine; Modeling; Mood Disorders; Moods; Motor Activity; National Institute of Mental Health; Nature; Netherlands; Neurologic Examination; Neuropsychology; Nomenclature; Overweight; Paper; Patient Self-Report; Pattern; Personality; Persons; Phase; Phenotype; Physical Examination; Preventive Intervention; Principal Component Analysis; Procedures; Protocols documentation; Psyche structure; Psychiatry; Psychology; Psychopathology; Psychophysiology; Public Health; Publications; Publishing; Recording of previous events; Reflex action; Research; Research Personnel; Resolution; Risk; Risk Factors; Role; Saliva; Salivary; Sampling; Series; Site; Sleep; Sleep Disorders; Social Anxiety Disorder; Specificity; Stress; Structure; Suicide attempt; Switzerland; Symptoms; Syndrome; Temperament; Testing; Time; United States National Institutes of Health; Universities; University Hospitals; Validation; Valsalva Maneuver; Work; Youth; actigraphy; anxiety spectrum disorders; base; blink reflexes; cardiovascular disorder risk; cardiovascular risk factor; clinical phenotype; cognitive testing; cohort; community setting; computer program; computerized; diaries; disease classification; disorder subtype; endophenotype; environmental stressor; family structure; follow-up; genetic analysis; genetic epidemiology; high risk; hypomania; immune function; mobile computing; mood regulation; novel; offspring; physical state; proband; prospective; recruit; sleep pattern; social; stability testing; suicidal risk; symptom cluster; trait; transmission process

The major aims of this project have been accomplished through the establishment of a large community-based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are near completion and analyses of the findings are underway. To date, about 600 probands and about 1200 of their relatives have completed the study, including over 150 children between the ages of 7-17. Approximately 600 individuals have also been evaluated at the NIH Clinical Center. Probands represent a large range of disorders including mood, anxiety, sleep, migraine, and cardiovascular in addition to controls. We are now completing interviews with relatives who had not previously participated in the study. During the past year, we have nearly completed recruitment of probands. We have continued to contact additional family members to enhance the participation rate and are remotely collecting measures including activity assessments and saliva for extracting genetics data. We have completed collection and genotyping of DNA samples obtained through the end of 2018, and began statistical genetic analyses. We are also continuing to follow-up families with diagnostic interviews, mobile assessments, and selected clinical assessments to test the stability of these measures over time and track their relationship with emerging mental and medical illness in probands and family members, especially offspring age 30 and under. We completed pilot testing of the computerized version of our diagnostic interview and other study assessments. We plan to complete the transition to computer acquisition of all of the key measures in the study and to develop computer programs to exploit the item-level data from diagnostic interviews and related measures. We have continued to devote substantial effort to the analysis and publication of findings from this study. During the past year, our analyses have been devoted to: (1) familial aggregation and coaggregation of core clinical phenotypes including suicide attempts, ADHD, sleep disorders, and migraine; (2) associations between mood and anxiety disorder subtypes and familial transmission of the core domains underlying mood and anxiety disorders including sleep patterns, cardiovascular risk factors, hypomanic traits, olfactory function, cognitive neuropsychological function, temperamental domains, and startle and autonomic reactivity; (3) cross validation of findings from our family study with that of a parallel family study in Lausanne, Switzerland; and (4) genetic analyses of copy number variation and polygenic risk scores for bipolar disorder (BD), major depression, sleep disorders and patterns, and migraine. In our analyses of biomarkers that were collected on both probands and relatives, we found there were significant associations between overweight and the atypical subtype of depression and an association for BMI/overweight between probands and relatives in our study of familial specificity of atypical depression (Glaus et al, 2019). Another important finding that emerged during the last year was that the familial aggregation of suicide attempts was primarily attributable to comorbid mental disorders including mood, substance and anxiety disorders, and that the familial diathesis underlying social anxiety disorder (SAD) confers an additional elevation in risk of suicide attempts (Ballard et al, 2019). We are following up this finding by evaluating the extent to which people with SAD have increased reactivity to environmental stressors, particularly those of a social nature. We have conducted both methodologic studies of the procedures and analyses of dynamic phenotypes derived from actigraphy and electronic diaries/ecological momentary assessment (EMA), to harmonize data across multiple sites including our collaborative study in Lausanne, Switzerland, Sydney, Australia, Amsterdam, Netherlands, and Hong King, China. We have now published some of the key methodologic and substantive papers on the core domains that can be extracted from EMA including stability, variability and reactivity, combining data from different research actigraphy devices, functional principal component analysis to compare the structure of multiple data sets, and fragmentation models to test stability of particular emotional and physical states (Lamers et al, 2018; Johns et al, 2019). We published the major paper from our mobile technology phenotypes based on combined EMA-Actigraphy that investigates the inter-relationships of motor activity, sleep, mood, and energy (Merikangas et al, 2019). Findings revealed that motor activity patterns have a central role on mood regulation, and subjective energy has a primary influence on motor activity and sleep, and that people with a history of BD have greater cross-domain reactivity. Follow-up of these findings will be critical to test the stability of the findings and the role of environmental influences on mood/anxiety reactivity. We are also analyzing the real time EMA data to identify triggers and precursors of migraine, core features of mood disorder subtypes, core domains that may discriminate ADHD from mania, and the role of sleep in mood disorders, migraine and cardiovascular diseases and risk factors. We are now sharing these procedures with investigators at Yale, University of Toronto, University Hospital Lausanne, and several other sites. Public Health Impact: Integration of the clinical, neuropsychological and psychophysiological measures within families will render an in-depth analysis of the biological mechanisms crucial for mood and anxiety disorders and their underlying diatheses. This will not only lead to a better understanding of these conditions and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: The initial findings of our study have major implications for etiology, treatment, course and nosology of mood and anxiety disorders. However, the work requires replication in larger samples, re-assessment to examine stability of the findings, and collaboration with other sites to cover the full range of the spectrum of mood disorders and increase the power of the study. In collaboration with other NIMH Intramural Research Program investigators, we plan to recruit more probands with BD in order to follow-up on our findings regarding the heritability and promising findings regarding circadian rhythm dysregulation as its core feature. We will also place renewed emphasis on enhancing participation of relatives either in person or remotely and longitudinal follow-up of families. We will continue to follow-up the families, particularly those with youth to fulfill the prospective longitudinal questions about the stability, incidence, consequences, course and remission from mood disorders.

该项目的主要目标是通过建立一项大型的以社区为基础的成年先证者家庭研究来实现的，先证者参与全面的临床和生物学评估，然后对其成年和儿童亲属进行可比较的评估。 先证者的招募和亲属的评估已接近完成，并对结果进行分析正在进行中。 迄今为止，已有约 600 名先证者及其约 1200 名亲属完成了这项研究，其中包括 150 多名 7 至 17 岁的儿童。 NIH 临床中心还对大约 600 人进行了评估。 除了对照之外，先证者还代表了一系列的疾病，包括情绪、焦虑、睡眠、偏头痛和心血管疾病。 我们现在正在完成对之前未参与该研究的亲属的采访。 在过去的一年里，我们几乎完成了先证者的招募。我们继续联系更多家庭成员以提高参与率，并正在远程收集包括活动评估和唾液在内的措施以提取遗传数据。我们已完成截至 2018 年底获得的 DNA 样本的收集和基因分型，并开始统计遗传分析。我们还继续通过诊断访谈、移动评估和选定的临床评估来跟踪家庭，以测试这些措施随着时间的推移的稳定性，并跟踪它们与先证者和家庭成员（尤其是 30 岁和 30 岁的后代）中新出现的精神和医学疾病的关系。在下面。我们完成了诊断访谈和其他研究评估的计算机化版本的试点测试。我们计划完成研究中所有关键指标向计算机采集的过渡，并开发计算机程序以利用诊断访谈和相关指标中的项目级数据。 我们继续投入大量精力来分析和发表这项研究的结果。在过去的一年里，我们的分析主要集中在：（1）家族聚集和核心临床表型的共聚集，包括自杀未遂、多动症、睡眠障碍和偏头痛； （2）情绪和焦虑障碍亚型与情绪和焦虑障碍核心领域的家族传播之间的关联，包括睡眠模式、心血管危险因素、轻躁狂特征、嗅觉功能、认知神经心理功能、气质领域以及惊吓和自主反应性； (3) 对我们的家庭研究结果与瑞士洛桑的平行家庭研究结果进行交叉验证； (4) 双相情感障碍 (BD)、重度抑郁症、睡眠障碍和模式以及偏头痛的拷贝数变异和多基因风险评分的遗传分析。在我们对先证者和亲属收集的生物标志物的分析中，我们发现超重和非典型抑郁症亚型之间存在显着关联，并且在我们的非典型抑郁症家族特异性研究中，先证者和亲属之间的BMI/超重存在显着关联（Glaus）等人，2019）。 去年出现的另一项重要发现是，自杀企图的家族聚集主要归因于共存精神障碍，包括情绪障碍、物质障碍和焦虑障碍，而社交焦虑障碍 (SAD) 的家族素质会导致自杀风险进一步升高。自杀未遂（Ballard 等，2019）。我们正在通过评估季节性情感障碍患者对环境压力源（尤其是社交压力源）的反应程度来跟踪这一发现。我们对源自体动记录仪和电子日记/生态瞬时评估 (EMA) 的动态表型进行了方法学研究，以协调多个地点的数据，包括我们在瑞士洛桑、澳大利亚悉尼、荷兰阿姆斯特丹的合作研究，以及中国香港。我们现在已经发表了一些关于可以从 EMA 中提取的核心领域的关键方法论和实质性论文，包括稳定性、变异性和反应性，结合来自不同研究体动记录设备的数据，功能主成分分析来比较多个数据集的结构，和碎片模型来测试特定情绪和身体状态的稳定性（Lamers 等人，2018；Johns 等人，2019）。我们发表了基于组合 EMA-Actigraphy 的移动技术表型的主要论文，研究了运动活动、睡眠、情绪和能量的相互关系（Merikangas 等人，2019）。 研究结果显示，运动活动模式对情绪调节具有核心作用，主观能量对运动活动和睡眠具有主要影响，并且有双相情感障碍病史的人具有更大的跨域反应性。这些发现的后续行动对于测试结果的稳定性以及环境影响对情绪/焦虑反应的作用至关重要。我们还分析实时 EMA 数据，以确定偏头痛的触发因素和前兆、情绪障碍亚型的核心特征、可能区分 ADHD 和躁狂症的核心领域，以及睡眠在情绪障碍、偏头痛和心血管疾病及危险因素中的作用。我们现在正在与耶鲁大学、多伦多大学、洛桑大学医院和其他几个地点的研究人员分享这些程序。 公共卫生影响： 家庭内临床、神经心理学和心理生理学措施的整合将深入分析对情绪和焦虑症及其潜在素质至关重要的生物学机制。这不仅将有助于更好地了解这些疾病并有助于识别常见的遗传机制，而且还可能导致开发新的治疗方案以及可能的策略，以预防和早期干预这些疾病风险较高的人。 未来计划： 我们研究的初步结果对情绪和焦虑障碍的病因学、治疗、病程和疾病分类学具有重大意义。然而，这项工作需要在更大的样本中进行复制，重新评估以检查研究结果的稳定性，并与其他站点合作以涵盖情绪障碍的全部范围并提高研究的力度。 我们计划与其他 NIMH 校内研究项目研究人员合作，招募更多双相情感障碍先证者，以便跟进我们关于遗传性的发现以及以昼夜节律失调为核心特征的有希望的发现。我们还将重新强调加强亲属亲自或远程参与以及对家庭的纵向跟踪。我们将继续对这些家庭进行随访，特别是那些有青少年的家庭，以解决有关情绪障碍的稳定性、发病率、后果、病程和缓解的前瞻性纵向问题。