Convergent Genetic and Genomic Analyses of Bipolar Disorder

双相情感障碍的融合遗传和基因组分析

• 批准号: 8245545
• 负责人: AYMAN H FANOUS
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245545
• 关键词: Affect; Algorithms; Binding Sites; Bioinformatics; Bipolar Disorder; Clinical assessments; Complex; DNA; DNA Sequence; Data; Data Set; Databases; Disease; Ethnic group; Family; Generations; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Genomics; Individual; Laboratories; Link; Methods; MicroRNAs; Mutation; National Institute of Mental Health; Patients; Promoter Regions; Psychiatry; Publishing; Reading; Reporting; Research; Rest; Risk; Sampling; Siblings; System; Technology; Testing; Time; Variant; Veterans; Work; base; cohort; density; disability; genetic risk factor; genetic variant; genome sequencing; genome wide association study; neuropsychiatry; next generation; novel; population based; transcription factor

DESCRIPTION (provided by applicant): Objective: To identify common and rare genetic variants which increase the risk of bipolar disorder (BP). Specific Objectives: 1. To discover both rare and common risk variants for BP by sequencing the whole genome of one affected individual from the 6 highest-density PIC families and the 36 highest-density families from the NIMH Genomics Initiative (42 patients in total), at ~32X coverage using second-generation short read DNA sequencers. 2. To rank the genes with greatest accumulations of deleterious variants discovered in SO 1 using a combination of bioinformatics criteria. We will implement an algorithm which prioritizes variants on the basis of functional changes and other features (e.g. exonic and promoter regions, and micro-RNA and transcription factor binding sites). This will be done in two steps: a. First, for variants discovered in regions linked to BP in that subject's family, and then b. In the rest of the genome. 3. Determine the complete DNA sequence of the 5 most promising genes in 500 BP cases and 500 normal controls by genome partitioning with Long PCR and second-generation short read DNA sequencers. 4. Impute novel variation into several large BP GWAS datasets. Currently, this only includes the Psychiatric GWAS Consortium (PGC, 7,481 cases and 9,250 controls). The Genomic Psychiatry Cohort and VA CSP#572 samples are also projected to be available. NB: This step will involve no new laboratory work or clinical assessments, but will only use existing GWAS marker data at that time. Background: Bipolar disorder is a major cause of disability amongst US veterans as well as worldwide. However, very little research in the genetics of BP has been done in the VA system. A number of genomewide association studies have reported several novel risk genes for BP but still explain only a small proportion of the genetic risk. Whole-genome sequencing has emerged in the last 2-3 years as the most comprehensive method to detecting genetic variation, and has recently resulted in several published findings of novel causes in several disorders. While prohibitively expensive only a few years ago, next-generation sequencing technologies have now made whole-genome sequencing possible, and it is currently being applied to complex diseases such as psychiatric illnesses. Proposed Methods: We plan to sequence the whole genomes of 42 patients with BP using the Illumina HiSeq 2000. To maximize the chance of identifying causative variants, these subjects will come from families in which there are at least 3 affected siblings. We will compare the genome sequences of these subjects to the sequence data in the 1000 Genomes Project, which is publicly available. We will prioritize sequence variants discovered based on their function. Based on our preliminary data, we expect to find thousands of deleterious variants which will not have been documented in established databases such as dbSNP. The 5 genes with the highest levels of deleterious variation will be sequenced in 500 cases and 500 controls using long PCR. Finally, we will attempt to impute the variants we discover in several large existing GWAS datasets, including one currently being collected in the VA system nationwide. PUBLIC HEALTH RELEVANCE: Bipolar disorder (BP) is a potentially devastating neuropsychiatric illness. There are an estimated 90,000 patients with BP in the VA system nationwide. There are currently no specific genetic sequence changes (mutations) known to cause illness across various ethnic groups, and a large proportion of patients do not respond to treatment adequately. Recently, we have developed the capacity to sequence the entire genomes of individuals. Finding potentially rare sequence changes that might cause the illness is a new and potentially powerful means to isolating the genetic risk factors for this illness. The identification of such mutations may provide vital clues to understanding not only the causes of the illness, but also to developing new treatments. In this project, we seek to determine the sequences of the entire genomes of individuals with BP and search for both common and rare mutations. We will then test the mutations that we discover in very large population- based samples.

描述（由申请人提供）： 目的：确定增加双相情感障碍（BP）风险的常见和罕见遗传变异。具体目标：1。通过使用第二代短读DNA测序仪对来自NIMH基因组学计划的6个最高密度PIC家族和36个最高密度家族（共42名患者）的1名受影响个体的全基因组进行测序，以~ 32 X覆盖率发现BP的罕见和常见风险变体。2.结合生物信息学标准，对SO 1中发现的有害变异累积最多的基因进行排序。我们将实现一种算法，该算法根据功能变化和其他特征（例如外显子和启动子区域，以及微小RNA和转录因子结合位点）对变体进行优先排序。这将通过两个步骤完成：a.首先，在该受试者家族中与BP相关的区域中发现的变异，然后是B。在基因组的其余部分。3.采用长片段PCR和第二代短片段测序仪对500例BP患者和500例正常对照进行基因组分区，测定5个最有希望的基因的全序列。4.将新的变异输入几个大型BP GWAS数据集。目前，这只包括精神病GWAS联盟（PGC，7，481例和9，250例对照）。基因组精神病学队列和VA CSP#572样本预计也将提供。注：此步骤将不涉及新的实验室工作或临床评估，但届时将仅使用现有的GWAS标记数据。背景：双相情感障碍是美国退伍军人以及全世界残疾的主要原因。然而，在VA系统中对BP的遗传学研究很少。一些全基因组关联研究已经报道了几个新的BP风险基因，但仍然只能解释一小部分遗传风险。全基因组测序在过去的2-3年中已经成为检测遗传变异的最全面的方法，并且最近已经导致了几种疾病中新原因的几项已发表的发现。虽然仅在几年前，下一代测序技术还非常昂贵，但现在已经使全基因组测序成为可能，目前正应用于精神疾病等复杂疾病。建议的方法：我们计划使用Illumina HiSeq 2000对42名BP患者的全基因组进行测序。为了最大限度地提高识别致病变异的机会，这些受试者将来自至少有3个受影响兄弟姐妹的家庭。我们将这些受试者的基因组序列与1000个基因组计划中的序列数据进行比较。我们将根据它们的功能对发现的序列变体进行优先排序。根据我们的初步数据，我们预计会发现数千种有害的变异，这些变异在dbSNP等已建立的数据库中没有记录。将使用长PCR对500例病例和500例对照中具有最高水平有害变异的5个基因进行测序。最后，我们将尝试估算我们在几个现有的大型GWAS数据集中发现的变体，包括目前在全国范围内收集的VA系统。 公共卫生相关性： 双相情感障碍（BP）是一种潜在的破坏性神经精神疾病。全国VA系统估计有9万名BP患者。目前还没有已知的特定基因序列变化（突变）会导致不同种族群体的疾病，而且很大一部分患者对治疗没有充分的反应。最近，我们已经开发出对个体的整个基因组进行测序的能力。寻找可能导致这种疾病的潜在罕见序列变化是一种新的和潜在的强大手段，可以隔离这种疾病的遗传风险因素。这些突变的鉴定不仅可以为理解疾病的原因提供重要线索，而且还可以开发新的治疗方法。在这个项目中，我们试图确定BP个体的整个基因组序列，并寻找常见和罕见的突变。然后我们将测试我们在非常大的基于人群的样本中发现的突变。