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

基本信息

批准号：
8694565
负责人：
Pablo V. Gejman
金额：
$ 17.64万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694565
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 DNA Repository DNA Resequencing DNA Sequence Data Dimensions Disease European Evaluation Exons Frequencies Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Genetic Risk Genetic Transcription Genetic Variation Genome Genomics Genotype Goals Heterogeneity Induced Mutation Investigation Left Light Mental disorders Methods Modeling Molecular Genetics Mutation National Institute of Mental Health Neurons Pathology Patients Population Predisposition Property Psychiatry Recurrence Relative (related person)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 public health relevance rare variant repository research study structural genomics treatment strategy

项目摘要

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，影响全球 1% 的人口，并且遗传对易感性有很强的影响。最近对 SZ 的遗传学研究，例如全基因组关联研究 (GWAS) 和结构基因组研究，取得了显着进展，但仍有很大一部分遗传风险无法解释，这表明应该探索替代模型。我们设计了一个靶向测序实验，通过在基因组间隔中选择编码和调控序列，并具有参与 SZ 的先验证据。我们的目标来自 (i) 位于 SZ 相关拷贝数变异 (CNV) 区间内的基因，或 (ii) 在 SZ 中表现出极端转录偏离的基因，总共约 600kb 的序列。我们建议对 SZ 分子遗传学 (MGS) 收集样本进行测序，并从基因组精神病学队列 (GPC) 中提取序列，从而产生包含 3,181 个 SZ 病例和 3,500 个匹配对照的大型欧洲血统 (EA) 发现样本。通过将我们的目标限制在深圳较小但可能丰富的区域相关的低频变异，我们既降低了显着性所需的统计阈值，又经济地允许大样本量，使我们能够最大程度地识别 SZ 的新关联。然后，我们将在 4,100 个 SZ 病例的剩余 GPC EA 样本中检查最热门的复制结果，并筛选 5,400 个对照。此外，我们建议通过对最有前途的候选者进行功能评估来添加另一个维度的信息。为了实现这一目标，在随后的初步探索性工作中，我们将从携带相关突变的患者和对照中产生诱导多能干细胞（iPSC）分化的神经元并进行表型表征。如果成功，我们的研究将确定基因、假定突变以及这些突变导致 SZ 病理的作用机制。通过这种方式，我们期望加深对 SZ 的理解，并提出新的、有针对性的假设进行测试。所有数据和生物材料将通过指定的 NIMH 存储库 (www.nimhgenics.org) 和 dbGaP (dbgap.ncbi.nlm.nih.gov) 快速共享。