1/2 An Integrative Genetic Investigation of Schizophrenia

1/2 精神分裂症的综合遗传学研究

• 批准号: 8206339
• 负责人: Pablo V. Gejman
• 金额: $ 56.74万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 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/8206339
• 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. PUBLIC HEALTH RELEVANCE: Schizophrenia is a disorder with largely unknown biology, and is also resilient to treatment. This project will identify gene expression characteristics associated with schizophrenia in a simple pharmacological cell model from a large sample of cases and controls. The knowledge gathered from our proposed study will yield light into the pathophysiology of schizophrenia, and may offer novel leads to new or improved knowledge-based treatment strategies.

描述（由申请人提供）：精神分裂症是一种常见的、严重的、高度遗传性的精神障碍，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，患有慢性和严重的失能症状，并且无法工作。全基因组关联研究（GWAS）已成功揭示与精神分裂症可重复相关的个体常见易感位点。然而，与大多数其他复杂疾病一样，事实证明，识别精神分裂症的潜在因果变异、风险基因和病因基因网络很困难。这些基因座中的许多风险变异可能本质上是监管性的。在这里，我们建议通过基于 SNP 基因型和 RNAseq 数据的综合基因组学方法来填补我们对精神分裂症病因学的生物学理解的空白，这些数据来自精神分裂症分子遗传学病例对照样本的大量淋巴母细胞系 (LCL)，其中包括丰富的人口统计和精神病学信息。表达特征将在基线时和用多巴胺扰动后生成，基于这样的假设：使用这种药理学相关试剂的细胞扰动将揭示在未扰动（基线）状态下无法检测到的病因学相关基因。我们提供了两个支持事实的证据：（1）LCL 和 GWAS 结果表达分析的信号汇聚在 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重要 GWAS 位点以及与精神分裂症相关的拷贝数变异中的许多基因的表达。我们的研究将利用正在进行的实验 (RC2MH90030)，该实验对来自同一样本的 LCL 的未刺激（基线）全基因组表达谱进行分析。我们将鉴定与精神分裂症相关的多巴胺反应转录本，分析潜在的调控 DNA 变异（即表达数量性状核苷酸，eQTN），并评估 eQTN 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，并对一组最重要的 eQTN 进行功能表征。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，并通过与抗精神病药物的作用机制建立联系，揭示潜在的病因机制，引领诊断分类和治疗领域的临床应用。 公共卫生相关性：精神分裂症是一种生物学原理很大程度上未知的疾病，并且对治疗也有抵抗力。该项目将在一个简单的药理学细胞模型中从大量病例和对照样本中识别与精神分裂症相关的基因表达特征。从我们提出的研究中收集的知识将为精神分裂症的病理生理学提供线索，并可能为新的或改进的基于知识的治疗策略提供新的线索。