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基因分析”，是响应 RFA 资助双相情感障碍样本收集工作的长期合作努力的延续。因此，我们提交原始研究小组当前的新申请，以继续合作，并继续对生成的数据进行下一个逻辑步骤分析。我们根据 NIMH FOA MH08-130 开发了“双相情感障碍国际队列集合”。在 R01MH085542（Smoller/Sklar，PI）和慈善资金的支持下，我们实施了一种表型稳健、快速且具有成本效益的样本收集方法。在资助的五年期间，我们储存了约 18,000 个病例和 16,000 个对照的 DNA，这些样本以前从未用于双相情感障碍 (BD) 的基因组研究。我们在此提出了一个独特样本的增强目标，以增加我们对 BD 的了解并保持这个高生产力团队的完整。这里研究的样本将是 GWAS 可用样本的两倍以上，并且将是首批使用外显子组芯片和外显子组测序分析罕见变异的样本之一。这些分析将为检测带来 BD 风险的网络和基因座提供显着增强的能力。在目标 1 中，我们将对 15,800 个病例和 18,598 个对照的独立队列进行基因组表征，通过常见单核苷酸多态性、拷贝数变异和罕见单核苷酸变异的关联研究来识别 BD 风险的高可信度遗传位点。我们将进一步利用这些数据探索针对两种特定临床情况的 BD 基因预测模型。在目标 2 中，我们将通过检查表型亚组、跨疾病关系、定量人格维度和神经认知，应用这些数据来表征基因型-表型关系的范围。我们的目标是更多地了解双相情感障碍的遗传学以及基因如何发挥作用来改变疾病风险。我们建议使用该领域最大、最全面研究的样本集来做到这一点，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.