Gene Expression in an African American Schizophrenia Dataset

描述(申请人提供)：精神分裂症(SZ)是一种常见的、严重的、高度遗传性的精神障碍。绝大多数患有SZ的患者在接受治疗后仍处于患病状态 发病初期，出现慢性和严重丧失工作能力的症状，无法工作。因此，需要以病理生理学为基础的治疗，改善生物学洞察力应该能够实现。全基因组关联研究已经成功地发现了与SZ相关的个体共同易感基因座，结果提示了许多和不同的可能的致病机制。事实证明，识别潜在的因果变异、风险基因和病因基因网络很困难，就像大多数其他复杂的疾病一样。由于许多与SZ(与其他复杂疾病)相关的GWASSNPs要么是基因间的，要么与明显的候选功能变异(如错义SNPs)无关，因此这些基因座上的许多风险变量似乎本质上是调节性的。这些观察促使我们检查了我们的SZ(MGS)病例对照样本的欧洲祖先(EA)分子遗传学样本(RC2MH90030)中的转录转录特征，该样本与以前的GWA结果趋同，涉及主要组织相容性(MHC)区域，并发现了新的基因。我们建议对非洲裔美国人(AA)MGS病例对照样本进行研究。许多关于SZ的遗传研究，包括GWAs，一直偏向于EA样本，由此产生的发现及其翻译效用可能不会完全推断到其他祖先群体。除了使SZ研究多样化以外，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，表达数量特征核苷酸，eQTN)，并评估它们与SZ的关联。然后，我们将在神经元组织中对淋巴母细胞系(LCL)的发现进行验证测试，并将 从功能上描述一组最重要的eQTN。我们的目标是检测针对AA样本的SZ易感基因(即在EA样本中检测不到)，并告知我们先前的EA发现(针对重叠的SZ易感基因)。这项拟议的研究有望确定影响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，揭示已识别的GWA基因座的原因基因，并使进一步研究潜在的病因学机制成为可能。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，以最大化这项研究投资的回报，不仅是在精神遗传学方面，而且是出于普遍的研究兴趣，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.