2/2 Targeted Sequencing and Functional Evaluation of Mutations in Schizophrenia

2/2 精神分裂症突变的靶向测序和功能评估

• 批准号: 9069531
• 负责人: Pablo V. Gejman
• 金额: $ 34.89万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9069531
• 关键词: 17q12; 1q21; 22q11; 3q29; Accounting; Affect; Biocompatible Materials; Biological; Biological Models; California; Cell Line; Cell model; Cells; Characteristics; Chicago; Chromosomes; Code; Collection; Complement; Copy Number Polymorphism; DNA Repository; DNA Resequencing; DNA Sequence; Data; Dimensions; Disease; European; Evaluation; Exons; Frequencies; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genomic approach; Genomics; Genotype; Goals; Health; Heterogeneity; Induced Mutation; Investigation; Left; Light; Methods; Modeling; Molecular Genetics; Mutation; National Institute of Mental Health; Neurons; Pathology; Patients; Population; Predisposition; Property; Psychiatry; Recurrence; Research; Risk; Role; Sample Size; Sampling; Schizophrenia; Site; Stem cells; Susceptibility Gene; Testing; Transcript; Universities; Variant; Work; base; cohort; database of Genotypes and Phenotypes; design; dosage; gene function; genome sequencing; genome wide association study; high risk; induced pluripotent stem cell; insertion/deletion mutation; lymphoblastoid cell line; novel; repository; research study; severe psychiatric disorder; structural genomics; targeted sequencing; transcriptome; treatment strategy; whole genome

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a severe psychiatric disorder that affects 1% of the population worldwide and has a strong genetic influence on susceptibility. Recent genetic investigations of SZ, such as genome-wide association studies (GWAS) and structural genomic studies have made remarkable progress but leave a substantial part of the genetic risk unexplained, suggesting alternative models should be explored. We have designed a targeted sequencing experiment, by selecting coding and regulatory sequence in genomic intervals with high prior evidence for involvement in SZ. Our targets come from (i) genes that reside within SZ- associated copy number variant (CNV) intervals, or (ii) genes that show extreme transcriptional departures in SZ, for a total of ~600kb of sequence. We propose sequencing sample from the Molecular Genetics of SZ (MGS) collection and extracting sequence from the Genomic Psychiatry Cohort (GPC), resulting in a large, combined European ancestry (EA) discovery sample of 3,181 SZ cases and 3,500 matched controls. By limiting our target to a region that is small but likely enriched for SZ associated low frequency variants, we both lower the statistical threshold required for significance, and economically allow for a large sample size, giving us maximal power to identify new associations for SZ. We will then examine top hits for replication in the remaining GPC EA sample of 4,100 SZ cases and screened 5,400 controls. In addition, we propose adding another dimension of information, by functional evaluation of our most promising candidates. To accomplish this goal, in subsequent initial, exploratory work, we will generate and phenotypically characterize induced pluripotent stem cell (iPSC)-differentiated neurons from patients harboring associated mutations and from controls. If successful, our study will identify genes, putative mutations, and a mechanism of action by which those mutations contribute to SZ pathology. In this way we expect to refine our understanding of SZ and advance new, focused hypotheses to be tested. All data and biological materials will be rapidly shared through the designated NIMH repository (www.nimhgenetics.org) and dbGaP (dbgap.ncbi.nlm.nih.gov).

描述（由申请人提供）： 精神分裂症（SZ）是一种严重的精神疾病，影响了全球1％的人口，并且对易感性具有强大的遗传影响。 SZ的最新遗传研究，例如全基因组关联研究（GWAS）和结构基因组研究，取得了显着的进步，但留下了无法解释的遗传风险的很大一部分，这表明应该探索替代模型。我们通过在基因组间隔中选择编码和调节序列，设计了一个有针对性的测序实验，并具有很高的先前证据以参与SZ。我们的目标来自位于SZ-相关拷贝数变体（CNV）间隔内的（i）基因，或（ii）在SZ中显示极端转录出发的基因，总计约600kb的序列。我们提出了从SZ（MGS）收集的分子遗传学中提出的测序样品，并从基因组精神病学队列（GPC）中提取序列，从而获得了3,181个SZ病例和3,500个匹配的对照组的大型欧洲血统（EA）发现样本。通过将我们的目标限制为小但可能富含SZ的区域 相关的低频变体，我们都降低了显着性所需的统计阈值，并且在经济上允许大量样本量，从而为我们提供了最大的能力来识别SZ的新关联。然后，我们将在剩余的4,100个SZ病例的GPC EA样本中检查最高点击以进行复制，并筛选5,400个对照。此外，我们建议通过对我们最有前途的候选人的功能评估来添加信息的另一个维度。为了实现这一目标，在随后的初始探索性​​工作中，我们将产生和表型来表征诱导的多能干细胞（IPSC）从具有相关突变和对照组中的患者的分化神经元。如果成功，我们的研究将确定基因，推定的突变以及这些突变有助于SZ病理学的作用机理。通过这种方式，我们希望能够完善我们对SZ的理解，并提高新的，重点的假设的测试。所有数据和生物材料将通过指定的NIMH存储库（www.nimhgenetics.org）和DBGAP（dbgap.ncbi.nlm.nih.gov）迅速共享。