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.

该项目的主要目的是通过建立大型社区基于社区的家庭研究，他们参与了全面的临床和生物学评估，然后对其成人和儿童亲戚进行了可比的评估。 招募概率和亲戚的评估即将完成，对调查结果的分析正在进行中。 迄今为止，大约有600个概率和约1200个亲戚已经完成了这项研究，其中包括150多名7-17岁之间的儿童。 在NIH临床中心还评估了大约600个人。 概率代表了许多疾病，包括情绪，焦虑，睡眠，偏头痛和心血管外。 我们现在正在与以前从未参加过研究的亲戚完成访谈。 在过去的一年中，我们几乎完成了招聘的招聘。我们继续联系其他家庭成员以提高参与率，并正在远程收集措施，包括活动评估和提取遗传学数据的唾液。我们已经完成了通过2018年底获得的DNA样品的收集和基因分型，并开始了统计遗传分析。我们还将继续跟进家庭进行诊断访谈，移动评估和选定的临床评估，以测试这些措施随时间的稳定性，并跟踪他们在证据和家人中，尤其是30岁及以下的后代中与新兴的精神和医学疾病的关系。我们完成了对诊断访谈和其他研究评估计算机版本的试点测试。我们计划完成对研究中所有关键措施的计算机获取的过渡，并开发计算机程序，以利用诊断访谈和相关措施中的项目级数据。 我们继续将大量努力用于分析和发布这项研究的结果。在过去的一年中，我们的分析一直致力于：（1）核心临床表型的家族聚集和凝聚，包括自杀尝试，ADHD，睡眠障碍和偏头痛； （2）情绪和焦虑症亚型与家族性情绪和焦虑症的家族传播之间的关联，包括睡眠模式，心血管危险因素，躁狂性特征，嗅觉功能，认知神经心理学功能，气质领域，气质领域以及暂停和自主反应性； （3）通过在瑞士洛桑（Lausanne）进行的一项平行家庭研究的调查结果交叉验证； （4）双相情感障碍（BD），严重抑郁症，睡眠障碍和模式以及偏头痛的拷贝数变化和多基因风险评分的遗传分析。在我们对概率和亲戚均收集的生物标志物的分析中，我们发现超重与非典型抑郁症亚型之间存在着显着关联，以及在我们对非洲类型的家族特异性研究中，概率与亲戚之间的BMI/超重缔合（Glaus等人，2019年）。 去年出现的另一个重要发现是，自杀尝试的家族性聚集主要归因于合并症，包括情绪，物质和焦虑症在内的精神障碍，以及基本的社交焦虑症（SAD）的家族性言论赋予了自杀企图风险的额外升高（Ballard等人，2019年）。我们正在通过评估SAD的人对环境压力，特别是具有社会性质的人的反应性的程度来跟进这一发现。我们既对源自行为的和电子日记/生态时刻评估（EMA）得出的动态表型的方法和分析进行了方法学研究，以协调跨多个地点的数据，包括我们在瑞士，瑞士，苏格兰，悉尼，澳大利亚，澳大利亚，阿姆斯特丹，纽约州和荷兰的协作研究。现在，我们已经就可以从EMA中提取的核心领域发表了一些关键方法论和实质性论文，包括稳定性，可变性和反应性，结合了来自不同研究的行为式设备的数据，功能性主成分分析，以比较多个数据集的结构，以及多个数据集的结构，以及测试特定情绪和身体状态的稳定性模型（Lamers et al，2018; Johns et al，2019年； 2019年）。我们根据基于EMA-EMA分类的组合进行了移动技术表型的主要论文，该论文研究了运动活动，睡眠，情绪和能量的相互关系（Merikangas等，2019）。 研究结果表明，运动活动模式在情绪调节中具有核心作用，主观能量对运动活动和睡眠有主要影响，并且具有BD病史的人具有更大的跨域反应性。这些发现的随访对于测试发现的稳定性以及环境影响对情绪/焦虑反应的作用至关重要。我们还正在分析实时EMA数据，以识别偏头痛的触发因素和前体，情绪障碍亚型的核心特征，可能将ADHD区分开的核心领域以及睡眠在情绪障碍，偏头痛和心血管疾病和心血管疾病中的作用。我们现在正在与耶鲁大学，多伦多大学，大学医院洛桑大学和其他几个地点的调查人员分享这些程序。 公共卫生影响： 家庭内的临床，神经心理学和心理生理措施的整合将对对情绪和焦虑症及其潜在核心的生物学机制进行深入分析。这不仅会导致对这些疾病的更好理解，并有助于确定常见的遗传机制，而且还可能导致新的治疗选择的发展以及预防和早期干预这些疾病风险升高的策略。 未来计划： 我们研究的最初发现对情绪和焦虑症的病因，治疗，课程和病因具有重大影响。但是，这项工作需要在较大的样本中复制，重新评估以检查发现的稳定性，并与其他站点进行协作，以涵盖情绪障碍的全部范围并增加研究的力量。 在与其他NIMH室内研究计划调查人员合作的情况下，我们计划招募更多使用BD的证据，以跟进有关遗传力和有关昼夜节律失调的发现的发现和有前途的发现，作为其核心特征。我们还将重新强调亲自或远程和纵向随访的亲戚的参与。我们将继续跟进这些家庭，尤其是那些有年轻人的家庭，以解决有关稳定，发病率，后果，课程和情绪障碍缓解的前瞻性纵向问题。