2/2- An Integrative Genetic Investigation of Schizophrenia

2/2- 精神分裂症的综合遗传学研究

• 批准号: 8305485
• 负责人: Harald Heinz Herbert Goring
• 金额: $ 22.39万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-21 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305485
• 关键词: Advocate; Affect; Amphetamines; Antipsychotic Agents; Architecture; Autopsy; Biological; Biology; Brain; Budgets; Cell Line; Cell model; Cells; Characteristics; Chromosomes, Human, Pair 6; Chronic; Classification; Cocaine; Collection; Complex; DNA; DNA Sequence; Data; Detection; Diagnostic; Disease; Dopamine; Drug Psychoses; Etiology; European; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; General Hospitals; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Human; Immune; Individual; Investigation; Knowledge; Letters; Light; Major Histocompatibility Complex; Massachusetts; Measurement; Modeling; Molecular Genetics; Molecular Profiling; Nature; Neurons; Nucleotides; Patients; Predisposition; Psychotic Disorders; Risk; SNP genotyping; Sampling; Schizophrenia; Signal Transduction; Specimen; Symptoms; System; Systems Biology; TCF7L2 gene; Testing; Tissues; Transcript; Validation; Variant; Work; autocrine; base; case control; clinical application; comparative genomic hybridization; cost effective; design; exome; follow-up; genome wide association study; genome-wide; improved; insight; knowledge base; lymphoblastoid cell line; neuroblastoma cell; novel; paracrine; relating to nervous system; repository; research study; response; trait; treatment strategy

DESCRIPTION (provided by applicant): Schizophrenia is a common, severe, highly heritable psychotic disorder for which biological insights and etiological knowledge-based treatments have yet to be achieved. The vast majority of patients suffering from schizophrenia remains ill after the initial episode, suffering from chronic and severely incapacitating symptoms, and are unable to work. Genome-wide association studies (GWAS) have been successful in uncovering individual common susceptibility loci reproducibly associated with schizophrenia. However, identifying the underlying causal variants, risk genes, and etiological gene networks have proven difficult for schizophrenia, like for most other complex disorders. It is likely that many risk variants in these loci are regulatory in nature. Here, we propose to fill the gap in our biological understanding of schizophrenia etiology through an integrative genomics approach based on SNP genotype and RNAseq data from a large collection of lymphoblastoid cell lines (LCLs) derived from the Molecular Genetics of Schizophrenia case-control sample, which includes rich demographic and psychiatric information. Expression signatures will be generated at baseline and after a perturbation with dopamine, predicated on the hypothesis that cell perturbation using this pharmacologically relevant agent will reveal etiologically relevant genes which are undetectable in the unperturbed (baseline) state. We present evidence of two supporting facts: (1) Signals from expression analysis of LCLs and GWAS results converge at the major histocompatibility complex region on chromosome 6. (2) Dopamine stimulation strongly regulates the expression of many genes located in genome-wide significant GWAS loci, and in copy number variants associated with schizophrenia. Our study will capitalize on an ongoing experiment (RC2MH90030) of unstimulated (baseline) genome-wide expression profiles of LCLs from the same sample. We will identify dopamine-responsive transcripts associated with schizophrenia, analyze the underlying regulatory DNA variants (i.e., expression quantitative trait nucleotides, eQTNs), and assess the association of eQTNs with schizophrenia. We will then perform validation testing of LCL findings in neural tissues, and will functionally characterize a set of most important eQTNs. The proposed study is expected to identify new loci influencing schizophrenia risk, reveal the causal genes in already identified GWAS loci, and shed light on the underlying etiological mechanisms by establishing a connection to the mechanisms of action of antipsychotics, spearheading clinical applications in the field for diagnostic classification and treatment.

描述（由申请人提供）：精神分裂症是一种常见的、严重的、高度遗传的精神病性障碍，其生物学见解和基于病因学知识的治疗尚未实现。绝大多数精神分裂症患者在初次发作后仍然患病，患有慢性和严重丧失能力的症状，并且无法工作。全基因组关联研究（GWAS）已经成功地发现了与精神分裂症相关的个体共同易感基因座。然而，确定潜在的因果变异，风险基因和病因基因网络已被证明是困难的精神分裂症，像大多数其他复杂的疾病。很可能这些基因座中的许多风险变异本质上是调节性的。在这里，我们建议填补差距，我们的生物学理解精神分裂症的病因，通过整合基因组学方法的基础上SNP基因型和RNAseq数据从一个大的集合淋巴母细胞系（LCL）来自精神分裂症的病例对照样本的分子遗传学，其中包括丰富的人口统计学和精神病学信息。表达特征将在基线处和用多巴胺扰动后产生，基于以下假设，即使用该干扰相关试剂的细胞扰动将揭示在未扰动（基线）状态下不可检测的病因学相关基因。我们提出了两个支持事实的证据：（1）LCL和GWAS结果表达分析的信号集中在6号染色体上的主要组织相容性复合体区域。(2)多巴胺刺激强烈调节位于全基因组显著GWAS位点的许多基因的表达，以及与精神分裂症相关的拷贝数变异。我们的研究将利用一个正在进行的实验（RC2MH90030）的未刺激（基线）全基因组表达谱的LCL从同一个样本。我们将鉴定与精神分裂症相关的多巴胺应答转录物，分析潜在的调控DNA变体（即，表达数量性状核苷酸，eQTNs），并评估eQTNs与精神分裂症的关联。然后，我们将对神经组织中的LCL结果进行验证测试，并将在功能上表征一组最重要的eQTN。这项拟议的研究预计将确定影响精神分裂症风险的新基因座，揭示已确定的GWAS基因座中的致病基因，并通过建立与抗精神病药物作用机制的联系来阐明潜在的病因机制，引领该领域的临床应用。诊断分类和治疗。