Gene Expression in an African American Schizophrenia Dataset

非裔美国人精神分裂症数据集中的基因表达

• 批准号: 8509028
• 负责人: Alan R Sanders
• 金额: $ 50.34万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-12 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509028
• 关键词: Adoption; African; African American; Architecture; Benefits and Risks; Bioinformatics; Biological; Biology; Cell Line; Characteristics; Chronic; Communities; Complex; DNA; DNA Sequence; Data; Data Set; Detection; Disease; European; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Variation; Genomics; Genotype; Grant; Histocompatibility; Immune; Individual; Investments; Knowledge; Laboratories; Light; Link; Linkage Disequilibrium; Meta-Analysis; Molecular Genetics; Molecular Profiling; Nature; Neurons; Nucleotide Mapping; Nucleotides; Pathway interactions; Patients; Population; Predisposition; Psychotic Disorders; Quality Control; Quantitative Trait Loci; Reading; Recording of previous events; Regulator Genes; Research; Research Project Grants; Risk; Sample Size; Sampling; Schizophrenia; Susceptibility Gene; Symptoms; Testing; Tissues; Transcript; Validation; Variant; Work; base; case control; data sharing; database of Genotypes and Phenotypes; follow-up; genome wide association study; genome-wide; improved; induced pluripotent stem cell; insight; interest; knowledge base; lymphoblastoid cell line; new technology; novel; programs; psychogenetics; repository; risk variant; sample collection; trait; transcriptomics; treatment strategy

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a common, severe, highly heritable psychotic disorder. The vast majority of patients suffering from SZ remains ill after the initial episode, suffering from chronic and severely incapacitating symptoms, and is unable to work. Thus, there is a need for pathophysiologically based treatments that improved biological insights should enable. Genome-wide association studies (GWAS) have been successful in uncovering individual common susceptibility loci reproducibly associated with SZ, with the results suggesting a numerous and diverse set of possible etiological mechanisms. Identifying the underlying causal variants, risk genes, and etiological gene networks has proven difficult, like for most other complex disorders. Because many GWAS SNPs associated with SZ (as with other complex disorders) are either intergenic or otherwise uncorrelated with obvious candidate functional variation such as missense SNPs, it appears likely that many risk variants in these loci are regulatory in nature. These observations prompted us to examine transcriptomic signatures in our European ancestry (EA) Molecular Genetics of SZ (MGS) case-control sample (RC2MH90030), which converged with previous GWAS results in implicating the major histocompatibility (MHC) region, and also identified novel genes. We propose here to study the African-American (AA) MGS case-control sample. Much of the genetic research on SZ, including GWAS, has been biased towards EA samples, and the resulting findings, and their translational utility, may not fully extrapolate to other ancestral groups. Besides merely diversifying SZ research beyond EAs, there also are significant scientific advantages in studying an AA sample. We will generate expression signatures via RNAseq to seek transcripts associated with SZ, analyze the underlying regulatory DNA variants (i.e., expression quantitative trait nucleotides, eQTNs), and assess their association with SZ. We will then perform validation testing of lymphoblastoid cell line (LCL) findings in neuronal tissues, and will functionally characterize a set of most important eQTNs. We aim at detecting SZ susceptibility genes specific to AA samples (i.e., undetectable in EA samples), and to inform our previous EA findings (for overlapping SZ susceptibility genes). The proposed study is expected to identify new loci influencing SZ risk, benefit from the reduced extent of linkage disequilibrium (LD) in Africans, reveal causal genes in already identified GWAS loci, and enable further study of the underlying etiological mechanisms. We will rapidly share our results and data with the scientific community through a dbGaP sponsored mechanism to maximize the return on this research investment not only in psychiatric genetics, but also due to general research interest since it wil provide the most detailed and precisely localized eQTNs map in an AA sample.

描述（由申请人提供）：精神分裂症（SZ）是一种常见、严重、高度遗传的精神障碍。绝大多数患有 SZ 的患者在接受治疗后仍然患病 初次发作时，患有慢性和严重失能症状，并且无法工作。因此，需要基于病理生理学的治疗，以提高生物学洞察力。全基因组关联研究 (GWAS) 已成功发现与 SZ 重复相关的个体常见易感位点，结果表明存在多种可能的病因机制。与大多数其他复杂疾病一样，识别潜在的因果变异、风险基因和病因基因网络已被证明是困难的。由于许多与 SZ 相关的 GWAS SNP（与其他复杂疾病一样）要么是基因间的，要么与明显的候选功能变异（例如错义 SNP）不相关，因此这些位点中的许多风险变异似乎本质上是调节性的。这些观察结果促使我们检查欧洲血统 (EA) SZ (MGS) 病例对照样本 (RC2MH90030) 中的转录组特征，该样本与之前的 GWAS 结果一致，暗示主要组织相容性 (MHC) 区域，并且还鉴定了新基因。我们在此建议研究非裔美国人 (AA) MGS 病例对照样本。许多关于 SZ 的基因研究，包括 GWAS，都偏向于 EA 样本，由此产生的结果及其转化效用可能无法完全推断到其他祖先群体。除了使 SZ 研究多样化到 EA 之外之外，研究 AA 样本也具有显着的科学优势。我们将通过 RNAseq 生成表达特征，以寻找与 SZ 相关的转录本，分析潜在的调控 DNA 变异（即表达数量性状核苷酸，eQTN），并评估它们与 SZ 的关联。然后，我们将对神经元组织中的类淋巴母细胞系 (LCL) 结果进行验证测试，并将 从功能上描述了一组最重要的 eQTN。我们的目标是检测 AA 样本特有的 SZ 易感基因（即在 EA 样本中检测不到），并为我们之前的 EA 研究结果提供信息（对于重叠的 SZ 易感基因）。拟议的研究预计将确定影响 SZ 风险的新基因座，受益于非洲人连锁不平衡 (LD) 程度的降低，揭示已确定的 GWAS 基因座中的因果基因，并能够进一步研究潜在的病因机制。我们将通过 dbGaP 赞助的机制迅速与科学界分享我们的结果和数据，以最大限度地提高这项研究投资的回报，这不仅是在精神遗传学方面，而且也是由于普遍的研究兴趣，因为它将在 AA 样本中提供最详细和精确定位的 eQTN 图。