Translational Studies of Cycling in Bipolar Disorder

描述（由申请人提供）：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。这种疾病的确切原因目前尚不清楚，尽管相当大的研究工作致力于这一目标，部分是由于疾病的复杂性，无论是在其表型和其病因。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是高度遗传的，但这种疾病的风险基因识别工作受到了低功率的阻碍。对双相情感障碍生物学基础的研究目前正在人类和动物身上取得进展，在较小程度上，或多或少是独立的。每一条独立的调查线（即，动物和人类研究）对近十年来见证的双相情感障碍病因学知识的增加做出了贡献。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错失机会。我们的小组已经为克服这一障碍奠定了基础，解决双相情感障碍的遗传病因，通过实施一个融合的功能基因组学方法，利用来自不同学科的多个信息来源，缩小双相情感障碍易感基因位点和基因的搜索，并增加指定候选基因作为疾病的因果因素的严格性和准确性。在本申请中，我们提出将该方法应用于双相情感障碍表型的不同特征的研究（例如，循环和转换），并通过在一个表型富集且可能更同质的双相情感障碍儿童发作患者样本中测试与疾病相关的新候选基因来扩展它。这项工作的目标是确定导致双相情感障碍出现的基因，并调节其最突出的特征：情绪周期性和转换。这些基因的鉴定可能会对双相情感障碍的未来产生许多影响，包括改善疾病的诊断方法，建立个性化的药物和心理治疗方法，并干预疾病的进展，并最终预防其发生。

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.