2/2- An Integrative Genetic Investigation of Schizophrenia

2/2- 精神分裂症的综合遗传学研究

基本信息

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
项目类别：
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

项目摘要

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，严重，高度可遗传的精神病障碍，生物学见解和基于病因的疗法尚未实现。最初发作后，绝大多数患有精神分裂症的患者仍然患有慢性且严重丧失能力的症状，无法工作。全基因组关联研究（GWAS）已成功地发现与精神分裂症可重复相关的个体常见易感性基因座。但是，确定基本的因果变异，风险基因和病因基因网络对于精神分裂症来说很难，例如大多数其他复杂疾病。这些基因座中的许多风险变异可能都是监管性的。在这里，我们建议通过基于SNP基因型和RNASEQ数据的整合基因组学方法来填补我们对精神分裂症病因的差距，并从大量淋巴细胞细胞系（LCLS）中得出，这些细胞系（LCLS）来自精神分裂症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上的信息。表达特征将在基线和多巴胺扰动后产生，这是基于以下假设：使用该药理相关的剂的细胞扰动将揭示与未渗透（基线）状态无法检测到的病因相关的基因。我们提供了两个支持事实的证据：（1）LCLS和GWAS结果的表达分析的信号在6染色体上的主要组织相容性复合物区域收敛。（2）多巴胺刺激强烈调节位于基因组范围内基因组显着的GWAS基因座的许多基因的表达，以及与Schizizoverrenia相关的拷贝数变化中。我们的研究将利用正在进行的实验（RC2MH90030）的未刺激（基线）全基因组表达曲线的LCL中。我们将确定与精神分裂症相关的多巴胺反应转录本，分析基本的调节DNA变异（即表达定量性状性状核苷酸，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发现进行验证测试，并在功能上表征一组最重要的EQTN。拟议的研究预计将鉴定出影响精神分裂症风险的新基因座，揭示已经鉴定出的GWAS基因座中的因果基因，并通过与抗精神病药的作用机制建立联系，率先将临床应用在现场进行诊断和治疗的临床应用，从而阐明了基本的病因机制。