Genetic and Neurobiologic Risk Factors for Bipolar Disorder Development

双相情感障碍发展的遗传和神经生物学危险因素

• 批准号: 7760112
• 负责人: KIKI D CHANG
• 金额: $ 58.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-08 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760112
• 关键词: Adolescence; Adolescent; Adult; Affect; Affective; Age; Alcohol or Other Drugs use; Alleles; Amygdaloid structure; Anxiety Disorders; Attention deficit hyperactivity disorder; Behavior; Behavioral; Biological; Biological Markers; Bipolar Disorder; Blood; Brain; Candidate Disease Gene; Characteristics; Child; Child Support; Childhood; Chronic; Code; Collaborations; Comorbidity; Control Groups; Cross-Sectional Studies; Data; Development; Disease; Disruptive Behavior Disorder; Early identification; Environment; Environmental Risk Factor; Etiology; Evaluation; Event; Factor Va; Family; Family Study; Family history of; First Degree Relative; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; Growth Factor; Growth Factor Gene; Health Care Costs; Heritability; Hippocampus (Brain); Human; Hyperactive behavior; Individual; Inherited; Intervention; Interview; Laboratories; Lead; Life; Life Stress; Link; Longitudinal Studies; Major Depressive Disorder; Manic; Mental Depression; Mood Disorders; Moods; Morbidity - disease rate; Neurobiology; Neurotransmitter Receptor; Normal Range; Outcome; Parents; Pathogenesis; Patients; Pharmaceutical Preparations; Population; Population Study; Positioning Attribute; Prevention; Principal Investigator; Psychiatry; Psychosocial Factor; Questionnaires; Recurrence; Relative (related person); Reporting; Research; Research Personnel; Resources; Retrospective Studies; Risk; Risk Factors; Risk Marker; Sampling; Scanning; Severities; Severity of illness; Siblings; Stress; Structure; Substance abuse problem; Suicide; Suicide attempt; Symptoms; Testing; Twin Multiple Birth; United States National Institutes of Health; Work; accomplished suicide; base; brain-derived growth factor; childhood bipolar disorder; cohort; design; early onset; endophenotype; executive function; experience; follow-up; genetic analysis; gray matter; high risk; mortality; neural circuit; neuroimaging; offspring; patient population; prevent; proband; programs; psychosocial; receptor density; repository; response; serotonin transporter; stressor; substance abuse treatment; suicidal risk; tool; trait

DESCRIPTION (provided by applicant): Bipolar disorder (BD) commonly begins during childhood or adolescence, and those with early onset typically have greater severity of illness and suicidality. Early identification of this disorder is paramount for implementing psychosocial and pharmacologic interventions that might prevent the full disorder. Due to the nonspecificity of early symptoms of BD, such as hyperactivity or depression, biologic markers that signify highest-risk for BD would aid in early identification as well as contribute to the understanding of BD pathogenesis. Children with BD have abnormalities in amygdalar volume and prefrontal-limbic circuits, but it is unclear if these abnormalities are present before the development of BD. Furthermore, polymorphisms of the serotonin transporter (5-HTT) and brain-derived neurotrophic growth factor (BDNF) genes may adversely affect these circuits and be risk factors for BD. In order to study the trait-status of these neurobiological abnormalities and their relationship to genetic polymorphisms, it is necessary to study a high-risk group of children before the development of BD, such as children of parents with BD ("bipolar offspring"). We propose to study 100 offspring from families having one or more parents with BD, comprised of 50 sibling pairs discordant for putative prodromal BD ("Prodromal Siblings"), and 30 singleton healthy controls. Prodromal Siblings will be children with depression and/or ADHD + moderate mood symptoms. All subjects will be carefully assessed by semi-structured interviews, clinician rated scales, and questionnaires relevant to family function and life stressors. Blood will be obtained from parents and siblings for genotyping polymorphism status of the 5-HTT and BNDF genes. Subjects will be scanned on a high-field (3T) magnet, obtaining amygdalar morphometric and functional MRI data in response to two separate affective probes designed to elicit activation of prefrontal-amygdalar circuits. Finally, subjects will be reassessed by interview 3 years after initial evaluation to assess for development of BD. By studying genetic and brain characteristics of high-risk discordant siblings before the development of full BD, we will be able to determine non-environmental risk factors for BD that are not caused by later events, such as substance abuse or recurrent mood episodes. We will also be able to determine possible gene-effects on brain structure and function in this cohort and create a repository for genetic and neuroimaging data that can be used for future longitudinal studies.

描述（由申请人提供）：双相情感障碍（BD）通常在儿童期或青春期开始，早期发病的人通常病情更严重，更有自杀倾向。早期识别这种疾病对于实施可能预防全面疾病的心理社会和药物干预措施至关重要。由于 BD 早期症状（例如多动或抑郁）的非特异性，表示 BD 风险最高的生物标志物将有助于早期识别并有助于了解 BD 发病机制。患有 BD 的儿童的杏仁核体积和前额叶边缘回路存在异常，但尚不清楚这些异常是否在 BD 发生之前就存在。此外，血清素转运蛋白 (5-HTT) 和脑源性神经营养生长因子 (BDNF) 基因的多态性可能会对这些回路产生不利影响，并成为 BD 的危险因素。为了研究这些神经生物学异常的性状状态及其与遗传多态性的关系，有必要研究BD发展前的高危儿童群体，例如双相情感障碍父母的孩子（“双相情感后代”）。我们建议研究 100 个来自有一个或多个父母患有 BD 的家庭的后代，其中包括 50 对与假定的前驱 BD 不一致的兄弟姐妹（“前驱兄弟姐妹”）和 30 个单身健康对照。前驱兄弟姐妹将是患有抑郁症和/或多动症+中度情绪症状的儿童。所有受试者都将通过半结构化访谈、临床医生评分量表以及与家庭功能和生活压力源相关的问卷进行仔细评估。将从父母和兄弟姐妹处获取血液，用于对 5-HTT 和 BNDF 基因的多态性状态进行基因分型。受试者将在高场 (3T) 磁铁上进行扫描，获得杏仁核形态测量和功能 MRI 数据，以响应两个独立的情感探针，这些探针旨在引发前额杏仁核回路的激活。最后，受试者将在初次评估 3 年后通过访谈进行重新评估，以评估 BD 的发展情况。通过研究完全双相情感障碍发生之前高危不和谐兄弟姐妹的遗传和大脑特征，我们将能够确定双相情感障碍的非环境危险因素，这些因素不是由后来的事件（例如药物滥用或反复情绪发作）引起的。我们还将能够确定该队列中可能的基因对大脑结构和功能的影响，并创建可用于未来纵向研究的遗传和神经影像数据存储库。