Gene Expression in an African American Schizophrenia Dataset

描述（由申请人提供）：精神分裂症（SZ）是一种常见的、严重的、高度遗传的精神病性障碍。绝大多数患有SZ的患者在治疗后仍然患病。 首次发病，患有慢性和严重失能症状，无法工作。因此，需要基于病理生理学的治疗，改善的生物学见解应该能够实现。全基因组关联研究（GWAS）已成功地揭示了个别常见的易感基因座与SZ的可重复性，结果表明一个众多的和不同的一套可能的病因机制。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，就像大多数其他复杂的疾病一样。由于许多与SZ相关的GWAS SNP（与其他复杂疾病一样）是基因间的，或者与明显的候选功能变异（如错义SNP）不相关，因此这些基因座中的许多风险变异在本质上可能是调节性的。这些观察结果促使我们在我们的欧洲血统（EA）SZ（MGS）病例对照样本（RC2MH 90030）中检查转录组特征，该样本与先前的GWAS结果一致，涉及主要组织相容性（MHC）区域，并且还鉴定了新基因。我们建议在这里研究非洲裔美国人（AA）MGS病例对照样本。许多关于SZ的遗传学研究，包括GWAS，都偏向于EA样本，由此产生的发现及其翻译效用可能无法完全外推到其他祖先群体。除了仅仅使SZ研究多样化之外，研究AA样本也有显著的科学优势。我们将通过RNAseq生成表达签名以寻找与SZ相关的转录本，分析潜在的调控DNA变体（即，表达数量性状核苷酸，eQTNs），并评估其与SZ的关联。然后，我们将对神经元组织中的淋巴母细胞样细胞系（LCL）结果进行验证测试，并将 在功能上表征一组最重要的eQTN。我们旨在检测AA样品特异性的SZ易感基因（即，在EA样品中检测不到），并告知我们以前的EA发现（重叠的SZ易感基因）。这项拟议的研究预计将确定影响SZ风险的新基因座，从非洲人连锁不平衡（LD）程度的降低中获益，揭示已经确定的GWAS基因座中的致病基因，并进一步研究潜在的病因机制。我们将通过dbGaP赞助的机制与科学界快速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，不仅在精神病学遗传学方面，而且由于一般的研究兴趣，因为它将提供AA样本中最详细和精确定位的eQTNs图谱。

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.