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

描述（由申请人提供）：该项目的总体目标是启动一项精神分裂症（SZ）基因表达的全基因组研究，目标是在具有全基因组关联研究（GWAS）数据的存储库样本中超过25,000个注释基因。该提案的基本假设是基因调控机制参与了SZ的病因学，基因表达数据将有助于解释SZ GWAS结果并指导实验室工作，包括大型重测序计划。AIM 1 -利用Illumina HT-12阵列在一个功率良好的样品中测定全基因组基因表达水平，该样品由爱泼斯坦巴尔病毒（EBV）转化的B淋巴细胞（淋巴母细胞样细胞系，LCLs）组成，来自1,011名严重感染病例和1,011名来自SZ分子遗传学（MGS）样品的精神病学筛选对照组。实验将充分关注质量控制（QC），实验设计将允许对遗传和非遗传变异进行系统分析。AIM 2 -寻找调节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，对于这些基因转录本，将测试基因表达样本（1,011例病例和1,011例对照）中表达水平与顺式snp之间的关系。下一步将在其余的MGS EA样本（1671例病例和1643例对照）中检测这些已鉴定的snp与SZ之间的关联。然而，反式eqtl的全基因组搜索与顺式eqtl相比，统计能力降低。虽然人类疾病中的基因表达领域正在加速发展，但本提案解决了SZ（和精神病学）遗传学中缺乏高性能微阵列表达研究的问题。本提案仅要求支持DNA转录的测量，及其统计和生物信息学分析。拟议的GWES将极大地增加这一公共样本的价值，这是dbGAP中NIMH访问最多的临床样本，极大地放大了拟议实验的整体影响。罗格斯大学细胞和DNA存储库（RUCDR）已经建立的LCL NIMH资源将被访问，基因表达结果将通过NIMH赞助的机制迅速与科学界共享。未来的计划包括将我们的基因表达研究扩展到全转录组，目的是整合基因组变异、DNA转录和蛋白质组学数据，与SZ遗传学（以及一般的生物医学科学）的研究有关，并参与SZ基因表达的meta分析。SZ是一种毁灭性的、昂贵的精神疾病，表现出复杂的基因。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，并通过激励基于机制的实验创造新的研究机会，例如，可以测试药理学的模型有望迅速导致新的治疗策略。

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.