Genetic and Neurobiologic Risk Factors for Bipolar Disorder Development

描述（由申请人提供）：双相情感障碍（BD）通常在儿童或青少年时期开始，早期发病的患者通常有更严重的疾病和自杀倾向。这种疾病的早期识别对于实施可能预防全面疾病的社会心理和药物干预至关重要。由于双相障碍的早期症状（如多动症或抑郁症）的非特异性，表明双相障碍最高风险的生物标志物将有助于早期识别，并有助于了解双相障碍的发病机制。双相障碍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双相障碍发展之前就存在。此外，血清素转运体（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，成为双相障碍的危险因素。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，有必要研究双相障碍发生前的高危儿童群体，如父母患有双相障碍的儿童（“双相后代”）。我们拟研究100名来自父母一方或一方以上患有双相障碍的家庭的后代，包括50对推定为前驱双相障碍的兄弟姐妹（“前驱兄弟姐妹”），以及30名单胎健康对照。前驱兄弟姐妹将是患有抑郁症和/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相关的问卷进行仔细评估。将从父母和兄弟姐妹处采集血液，检测5-HTT和BNDF基因的基因分型多态性状态。受试者将在高场（3T）磁体上进行扫描，获得杏仁核形态测量和功能MRI数据，以响应两个单独的情感探针，这些探针旨在引发前额叶-杏仁核回路的激活。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，以评估双相障碍的发展情况。通过研究高危不协调兄弟姐妹在完全双相障碍发展之前的遗传和大脑特征，我们将能够确定非环境双相障碍的危险因素，这些因素不是由后来的事件引起的，如药物滥用或反复发作的情绪发作。我们还将能够确定这一队列中可能的基因对大脑结构和功能的影响，并创建一个遗传和神经成像数据库，可用于未来的纵向研究。

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.