2/2- An Integrative Genetic Investigation of Schizophrenia

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最初发作后仍处于疾病状态，患有慢性和严重丧失行为能力的症状，并且无法工作。全基因组关联研究（GWAS）已经成功地揭示了与精神分裂症可重复相关的个体共同易感位点。然而，像大多数其他复杂疾病一样，鉴定精神分裂症的潜在因果变异、风险基因和致病基因网络已被证明是困难的。很可能这些基因座中的许多风险变异本质上是调控的。在这里，我们建议通过基于来自精神分裂症病例对照样本的大量淋巴母细胞样细胞系（LCLs）的分子遗传学的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学的生物学理解的空白，这些样本包括丰富的人口统计学和精神病学信息。表达特征将在基线和多巴胺扰动后产生，这是基于这样的假设，即使用这种药理学上相关的药物扰动细胞将揭示在未扰动（基线）状态下无法检测到的病原学上相关的基因。我们提出了两个支持事实的证据：(1)LCLs表达分析和GWAS结果的信号汇聚在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许多位于全基因组重要GWAS位点的基因的表达，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项正在进行的实验（RC2MH90030），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，分析潜在的调节性DNA变异（即表达数量性状核苷酸，eQTNs），并评估eQTNs与精神分裂症的关系。然后，我们将对神经组织中的LCL结果进行验证测试，并将对一组最重要的eqtn进行功能表征。该研究预计将发现影响精神分裂症风险的新基因座，揭示已经确定的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，从而在诊断分类和治疗领域的临床应用中发挥先锋作用。

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.