1/2 Genomic Strategies to Identify High-impact Psychiatric Risk Variants

1/2 识别高影响精神病风险变异的基因组策略

• 批准号: 8806391
• 负责人: NELSON B. FREIMER
• 金额: $ 175.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-23 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806391
• 关键词: Adult; Affect; American; Base Sequence; Bioinformatics; Biological; Biological Assay; Biology; Bipolar Disorder; Brain; Cells; Chromatin; Code; Collaborations; Costa Rican; Data; Data Storage and Retrieval; Disease; Disease susceptibility; Exons; Fibroblasts; Finland; Founder Generation; Frequencies; Functional RNA; Genetic; Genetic Transcription; Genome; Genomics; Genotype; Goals; Grant; High-Throughput Nucleotide Sequencing; Individual; Joints; Measures; Netherlands; Neurons; Nucleic Acid Regulatory Sequences; Patients; Phenotype; Population; Probability; Psychiatry; Psychotic Disorders; Relative (related person); Reporter; Research Personnel; Role; Running; Sampling; Sampling Studies; Schizophrenia; Series; Site; Staging; Testing; Transposase; Uncertainty; United States National Institutes of Health; Validation; Variant; Work; base; case control; disorder control; endophenotype; epigenomics; exome; functional genomics; gene function; genetic association; genetic pedigree; genetic variant; genome sequencing; genome wide association study; genome-wide; member; nerve stem cell; neurodevelopment; novel; public health relevance; rare variant; research study; risk variant; trait; transcriptomics; validation studies; working group

 DESCRIPTION (provided by applicant): Schizophrenia (SCZ) and bipolar disorder (BP) are the major adult psychotic disorders; uncertainty about their relationship is a central issue in psychiatry. By discovering variants with a high impact on either or both disorders (or on their endophenotypes) we can transform our understanding of their biology. This multisite project, from investigators with a track record of successful collaboration, will leverage exceptional, extensively phenotyped pedigree and population samples and integrate a combination of bioinformatics and experimental genomics approaches to identify such variants and demonstrate their relationship to these diseases. We will proceed through three steps: (1) Detect novel variants by whole genome sequencing (WGS) of discovery samples from ethnically homogenous populations; (2) Prioritize genome regions for further studies of these variants, using bioinformatics and functional genomics analyses; (3) Identify disease related variants through (a) imputation-based association analyses in very large case/control samples from the same populations and (b) validation of associated and predicted-deleterious variants using novel high-throughput functional assays. The WGS discovery sample includes SCZ, BP, and control individuals from Finland (FIN) and the Netherlands (NL). We will analyze their variants using a pipeline already implemented by our group to analyze the completed WGS of BP pedigrees from recently bottlenecked Latin American founder populations. The majority of our WGS samples derive from such founder populations; as we have shown previously this creates a high probability of detecting deleterious variants in these samples. WGS will detect a huge number of variants, most of unknown functional significance. We will thus narrow our focus to regions (coding and non-coding) most likely relevant to SCZ and BP, using two approaches: (1) Bioinformatics to prioritize regions previously implicated in these disorders (e.g. GWAS or CNV loci, or variants highlighted in prior sequencing studies including that of our BP pedigrees) and candidate regulatory regions (through analyses of ENCODE or other reference data); (2) Sequencing-based assessments of transcriptomic and epigenomic variation that we will conduct in two unique samples relevant to our phenotypes: fibroblasts from affected and unaffected members of our BP pedigrees; and neuronal and neuronal progenitor cells from reference individuals. We will then leverage very large, genotyped case/control samples available from the same populations as our discovery samples (or closely related ones) to accurately impute the novel variants from our prioritized regions; this will enable us to identify associations with SCZ, BP, and/or endophenotypes. Finally, in an initial validation study, we will use a novel high-throughput sequence-based reporter assay to evaluate the function of putative regulatory variants highlighted by our bioinformatics pipeline or by our association analyses.

 描述（由申请人提供）：精神分裂症（SCZ）和双相情感障碍（BP）是主要的成人精神病性障碍;对它们之间关系的不确定性是精神病学的中心问题。通过发现对其中一种或两种疾病（或其内在表型）具有高度影响的变体，我们可以改变我们对其生物学的理解。这个多地点项目，来自具有成功合作记录的研究人员，将利用特殊的，广泛的表型谱系和人群样本，并整合生物信息学和实验基因组学方法的组合，以识别这些变异并证明它们与这些疾病的关系。我们将通过三个步骤进行：（1）通过全基因组测序（WGS）从种族同质人群中发现样本来检测新的变异;（2）使用生物信息学和功能基因组学分析来优先考虑基因组区域，以进一步研究这些变异;（3）通过（a）在来自相同群体的非常大的病例/对照样品中进行基于插补的关联分析和（B）使用新的高通量功能测定验证相关的和预测的有害变体。WGS发现样本包括来自芬兰（FIN）和荷兰（NL）的SCZ、BP和对照个体。我们将使用我们小组已经实施的管道来分析它们的变体，以分析来自最近检查的拉丁美洲创始人人群的BP谱系的完整WGS。我们的大多数WGS样本来自这样的创始人群体;正如我们之前所示，这使得在这些样本中检测到有害变体的概率很高。WGS将检测到大量的变体，其中大多数具有未知的功能意义。因此，我们将把重点缩小到区域（编码和非编码）最可能与SCZ和BP相关，使用两种方法：（1）生物信息学优先考虑先前与这些疾病有关的区域（例如GWAS或CNV基因座，或在先前测序研究中突出显示的变体，包括我们的BP家系）和候选调控区（通过分析ENCODE或其他参考数据）;（2）转录组和表观基因组变异的基于测序的评估，我们将在与我们的表型相关的两个独特样品中进行：来自我们BP谱系的受影响和未受影响成员的成纤维细胞;以及来自参考个体的神经元和神经元祖细胞。然后，我们将利用来自与我们的发现样本（或密切相关的样本）相同人群的非常大的基因型病例/对照样本，准确地估算来自我们优先区域的新变体;这将使我们能够识别与SCZ的关联， BP和/或内表型。最后，在初步验证研究中，我们将使用一种新的高通量基于序列的报告基因检测方法来评估我们的生物信息学管道或我们的关联分析所强调的推定调控变体的功能。