Genetic and Neurobiologic Risk Factors for Bipolar Disorder Development

描述(由申请人提供)：双相情感障碍(BD)通常始于儿童或青春期，早期发病的人通常有更严重的疾病和自杀倾向。早期识别这种疾病对于实施心理社会和药物干预措施是至关重要的，这些干预措施可能会预防全面的疾病。由于BD早期症状的非特异性，如多动或抑郁，标志BD最高风险的生物标志物将有助于BD的早期识别以及有助于了解BD的发病机制。患有BD的儿童杏仁核体积和前额叶-边缘环路异常，但尚不清楚这些异常是否在BD发生之前就存在。此外，5-羟色胺转运体(5-HTT)和脑源性神经营养生长因子(BDNF)基因的多态性可能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特征状态及其与遗传多态的关系，有必要对BD发生前的高危儿童进行研究，例如父母患有BD的儿童(BD)。我们建议研究100名来自父母中有一人或多人患有BD的家庭的子女，其中包括50对可能患有前驱BD的兄弟姐妹(“前驱兄弟姐妹”)，以及30名单身健康对照。前驱兄弟姐妹将是有抑郁和/或ADHD+中度情绪症状的儿童。所有受试者将通过半结构化访谈、临床医生评定量表和与家庭功能和生活压力源相关的问卷进行仔细评估。血液将从父母和兄弟姐妹那里获得，用于5-HTT和BNDF基因的基因多态状态的基因分型。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测器，这些探测器旨在诱导前额叶-杏仁核电路的激活。最后，在初步评估3年后，将通过访谈对受试者进行重新评估，以评估BD的发展。通过在完全BD发展之前研究高危不和谐兄弟姐妹的遗传和大脑特征，我们将能够确定BD的非环境风险因素，这些因素不是由后来的事件引起的，例如药物滥用或反复出现的情绪发作。我们还将能够在这个队列中确定可能的基因对大脑结构和功能的影响，并创建一个可用于未来纵向研究的遗传和神经成像数据存储库。

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.