3/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder

 描述(由申请人提供)： 这笔赠款名为“双相情感障碍国际队列收集的遗传分析”，是为响应双相情感障碍样本收集的RFA而资助的长期合作努力的继续。因此，我们提交了原调查组目前的新申请，以继续合作，并对正在产生的数据进行下一个合乎逻辑的步骤分析。我们根据NIMH FOA MH08-130制定了“双相情感障碍国际队列集合”。在R01MH085542(斯莫勒/斯克拉尔，PI)和慈善基金的赞助下，我们实施了一种典型的稳健、快速和具有成本效益的样本收集方法。在五年的拨款期间，我们保存了约18,000例病例和16,000名对照的DNA，这些病例和对照以前从未用于双相情感障碍(BD)的基因组研究。我们在这里以一个独特的样本提出了增强的AIMS，以增加我们对BD的了解，并保持这支高生产率的团队不受影响。这里研究的样本将是GWAS现有样本的两倍多，并将是第一批使用外显子芯片和外显子测序分析稀有变异的样本之一。这些分析将为检测具有BD风险的网络和位置提供显著增强的能力。在目标1中，我们将对15,800例患者和18,598名对照的独立队列进行基因组特征分析，通过对常见的单核苷酸多态、拷贝数变异和罕见的单核苷酸变异的关联研究，确定BD风险的高置信度遗传基因座。我们将进一步使用这些数据来探索两种特定临床情景下BD的基因预测模型。在目标2中，我们将应用这些数据通过检查表型亚群、交叉障碍关系、量化人格维度和神经认知来表征基因型-表型关系的频谱。我们的目标是更多地了解BD的遗传学以及基因可能如何作用于改变疾病风险。我们建议使用该领域最大和最全面研究的样本收集来完成这项工作，其中包括遗传和表型风险因素。

 DESCRIPTION (provided by applicant): The grant, "Genetic Analysis of the International Cohort Collection for Bipolar Disorder", is continuation of a long-standing collaborative effort funded in response to an RFA for sample collections in bipolar disorder. We are thus submitting the current new application from the original group of investigators to continue the collaboration and proceed to its next logical step analyses of data being generated. We developed the "International Cohort Collection for Bipolar Disorder" in response to a NIMH FOA MH08-130. Under the auspices of R01MH085542 (Smoller/Sklar, PIs) and philanthropic funding we implemented a phenotypically robust, rapid, and cost effective method for sample collection. During the five years of the grant we have banked DNA from ~18,000 cases and 16,000 controls never previously used for genomic study of bipolar disorder (BD). We propose here enhanced aims in a unique sample to increase our knowledge of BD and to keep this highly productive team intact. The samples studied here will more than double the available samples for GWAS, and will be among the first to analyze rare variants using exome chip and exome sequencing. These analyses will provide substantially enhanced power for detection of networks and loci that confer BD risk. In Aim 1 we will perform a genomic characterization of an independent cohort of 15,800 cases and 18,598 controls to identify high confidence genetic loci for risk of BD through association study of common single nucleotide polymorphisms, copy number variants, and rare single nucleotide variants. We will further use the data to explore genetic prediction models for BD for two specific clinical scenarios. In Aim 2 we will apply these data to characterize the spectrum of genotype-phenotype relationships by examining phenotypic subgroups, cross- disorder relationships, quantitative personality dimensions, and neurocognition. Our goal is to learn more about the genetics of BD and how genes might act to alter disease risk. We propose to do this using the largest and most comprehensively studied sample collection in the field that includes both genetic and phenotypic risk factors.