Translational Studies of Cycling in Bipolar Disorder

描述(申请人提供)：双相情感障碍是一种常见的精神疾病，对受影响的个人、他们的家庭和社会造成毁灭性的后果。尽管致力于这一目标的大量研究工作致力于这一目标，但这种疾病的确切原因目前尚不清楚，部分原因是这种疾病的表型和病因都很复杂。由于这种复杂性，尽管双胞胎和收养研究清楚地表明双相情感障碍具有高度的遗传性，但这种疾病的风险基因识别努力一直受到低功率的阻碍。目前，对双相情感障碍的生物学基础的研究在人类身上取得了进展，在动物身上也取得了进展，或多或少是独立的。每一项独立的调查(即动物和人类研究)都有助于在过去十年中见证双相情感障碍病因学知识的不断增长。然而，现在很明显，这两条研究路线之间缺乏整合正在阻碍风险基因识别的步伐，或者更准确地说，构成了优化基因发现方法的机会。我们的团队已经为克服这一障碍，解决双相情感障碍的遗传病因奠定了基础，通过实施融合功能基因组学方法，利用来自不同学科的多个信息来源来缩小双相情感障碍易感基因和基因的搜索范围，并提高指定候选基因作为疾病病因的严格性和准确性。在目前的应用中，我们建议将这一方法应用于双相情感障碍表型的不同特征(例如，循环和转换)的研究，并通过在表型丰富且可能更同质的儿科双相情感障碍患者样本中测试与疾病相关的新候选基因来扩展这一方法。这项工作的目标是确定导致双相情感障碍出现的基因，并调节其最显著的特征：情绪周期性和转换。这些基因的确定可能会对双相情感障碍的未来产生许多后果，包括改进对这种疾病的诊断方法，为疾病的进展建立单独量身定制的药物和心理社会治疗和干预，并最终防止其发生。

DESCRIPTION (provided by applicant): Bipolar disorder is a common psychiatric illness with devastating consequences for affected individuals, their families, and society. The exact causes of this illness are presently not known, despite considerable research effort dedicated to this objective, in part due to the complexity of the illness, both in its phenotypes and its etiology. Due to this complexity, and although twin and adoption studies clearly demonstrate that bipolar disorder is highly heritable, risk-gene- identification efforts for this illness have been hampered by low power. Research into the biological basis of bipolar disorder is currently advancing in humans and--to a lesser extent--in animals, more or less independently. Each independent line of investigation (i.e., animal and human studies) is contributing to the incremental gains in knowledge of bipolar disorder etiology witnessed in the last decade. Yet, it is now clear that the lack of integration between these two lines of investigation is hindering the pace of risk-gene identification or, perhaps more accurately, constitutes a missed opportunity for optimizing the approach to gene discovery. Our group has laid the foundation for overcoming this barrier to resolving the genetic etiology of bipolar disorder by implementing a convergent functional genomics approach that capitalizes on multiple sources of information from various disciplines to narrow the search for bipolar disorder susceptibility loci and genes, and increase the stringency and accuracy of designating a candidate gene as a causal factor in the illness. In the present application, we propose to apply this methodology to the study of distinct features of the bipolar disorder phenotype (e.g., cycling and switching), and extend it by testing novel candidate genes for association with the illness in a phenotypically enriched and presumably more homogeneous--sample of patients with pediatric onset of bipolar disorder. The goal of this work is to identify the genes that contribute to the emergence of bipolar disorder and regulate its most prominent features: mood cyclicity and switching. The identification of these genes may have numerous consequences for the future of bipolar disorder, including the improvement of diagnostic approaches to the illness, the construction of individually tailored pharmacological and psychosocial treatments for and interventions in the progression of the illness, and, ultimately, the prevention of its occurrence.