Joint Mapping of Genome-Wide Gene Expression and Association in a Schizophrenia D

描述（由申请人提供）：该项目的主要目标是启动精神分裂症（SZ）基因表达的全基因组研究，目标是在具有可用全基因组关联研究（GWAS）数据的储存库样本中超过25，000个注释基因。该建议的基本假设是，基因调控机制参与了SZ的病因，基因表达数据将有助于解释SZ GWAS结果和指导实验室工作，包括大型重新测序计划。具体目标是：目的1 -利用Illumina HT-12阵列在一个由Epstein巴尔病毒（EBV）转化的B淋巴细胞（类淋巴母细胞系，LCL）组成的高效能样本中确定全基因组基因表达水平，该样本来自1,011例严重受影响的病例和1,011例来自SZ分子遗传学（MGS）样本的精神病学筛选对照。实验将在充分注意质量控制（QC）的情况下进行，实验设计将允许系统分析遗传和非遗传方差。目的2 -寻找调控SZ相关基因表达的eQTL。首先，将寻找显示病例-对照差异的表达序列，并且对于这些基因转录物，将测试基因表达样品（1，011例病例和1，011例对照）中表达水平与顺式SNP之间的关联。接下来，将在剩余的MGS EA样本（1，671例病例和1，643例对照）中测试这些鉴定的SNP与SZ之间的关联。还将进行全基因组范围的反式eQTL搜索，然而，与顺式eQTL相比，其统计功效降低。虽然人类疾病的基因表达领域正在加速发展，但该提案解决了SZ（和精神病）遗传学中缺乏强大的微阵列表达研究的问题。该提案仅要求支持DNA转录的测量及其统计和生物信息学分析。拟议的GWES将大大增加这个公共样本的价值，这个公共样本是dbGAP中NIMH最常用的临床样本，大大放大了拟议实验的整体影响。将访问罗格斯大学细胞和DNA储存库（RUCDR）已经建立的LCL NIMH资源，并通过NIMH赞助的机制与科学界迅速分享基因表达结果。未来的计划包括将我们的基因表达研究扩展到全转录组，目的是整合与SZ遗传学（和一般生物医学科学）研究相关的基因组变异，DNA转录和蛋白质组学数据，并参与SZ基因表达的荟萃分析。SZ是一种毁灭性的和昂贵的精神疾病，表现出复杂的遗传学。对表达和GWAS数据的联合分析有望发现SZ易感性的机制，否则这两种方法都无法单独发现SZ易感性，并通过激发基于机制的实验创造新的研究机会，例如，药理学可以被测试的模型有望迅速导致新的治疗策略。 公共卫生相关性：本研究旨在揭示精神分裂症患者与对照组之间基因表达差异的信息，它们与先前研究的遗传变异的关系，以及它们的联合分析。除了为生物学的重要领域提供信息外，该研究还特别旨在更好地了解遗传对精神分裂症的影响，作为更好地了解疾病如何发展的一种手段。这些知识应有助于预防和治疗这种毁灭性和昂贵的疾病。

DESCRIPTION (provided by applicant): The broad goal of this project is to initiate a genome-wide study of gene expression of schizophrenia (SZ), targeting over 25,000 annotated genes, in a repository sample with available genome-wide association study (GWAS) data. The basic hypothesis of this proposal is that gene regulation mechanisms are involved in the etiology of SZ, and that gene expression data will be instrumental to the interpretation of SZ GWAS results and for guiding laboratory efforts, including large re-sequencing initiatives. The specific aims are: AIM 1 - Determine genome-wide gene expression levels utilizing the Illumina HT-12 array in a well-powered sample comprised of Epstein Barr Virus (EBV) transformed B lymphocytes (lymphoblastoid cell lines, LCLs) from 1,011 severely affected cases and 1,011 psychiatrically screened controls from the Molecular Genetics of SZ (MGS) sample. The experiment will proceed with full attention to quality control (QC) and the experimental design will allow for the systematic analysis of genetic and non-genetic variance. AIM 2 - Search for eQTLs that regulate the expression of genes associated with SZ. First, expressed sequences that show case-control differences will be sought, and for these gene transcripts, association between the expression levels and SNPs in cis in the gene expression sample (1,011 cases and 1,011 controls) will be tested. Next association between these identified SNPs and SZ will be tested in the rest of the MGS EA sample (1,671 cases and 1,643 controls). A genome-wide search for trans eQTLs will also be performed, however, with decreased statistical power compared to cis eQTLs. While the field of gene expression in human disease is growing at an accelerated pace, this proposal addresses the dearth of well-powered microarray expression studies in SZ (and psychiatric) genetics. This proposal only asks for support for the measurements of DNA transcription, and statistical and bioinformatic analyses thereof. The proposed GWES will greatly augment the value of this public sample, which has been the most accessed clinical sample for NIMH in dbGAP, greatly amplifying the overall impact of the proposed experiments. An already established LCL NIMH resource at the Rutgers University Cell and DNA Repository (RUCDR) will be accessed, and the gene expression results will be rapidly shared with the scientific community through an NIMH sponsored mechanism. Future plans include extending our study of gene expression to the full transcriptome with the aim of integrating genome variation, DNA transcription, and proteomic data relevant to the study of SZ genetics (and biomedical sciences in general), and participating in meta-analyses of gene expression in SZ. SZ is a devastating and costly psychiatric disorder exhibiting complex genetics. The joint analysis of expression and GWAS data is expected to lead to discoveries of mechanisms of SZ susceptibility otherwise obscured to either method in isolation, and create new research opportunities by motivating mechanistically based experiments, e.g., models where pharmacology can be tested hopefully rapidly leading to new treatment strategies. PUBLIC HEALTH RELEVANCE: This study aims to uncover information about differences in gene expression between individuals with schizophrenia versus controls, their relationship to previously studied genetic variation, and the joint analysis thereof. Besides informing important areas of biology, the study especially aims to better understand genetic contributions to schizophrenia, as a means to better understand how disease develops. This knowledge should assist in efforts to prevent and treat this devastating and costly illness.