3/3 Sequencing and Trans-Diagnostic Phenotyping of Severe Mental Illness in Diverse Populations

项目摘要 在这项新的、没有资金支持的研究中，我们将利用过去15年精神病学的经验教训。 基因组。基于这些经验教训，我们提出了一套特别新颖和重要的目标，以进一步 了解精神疾病的基因结构。我们建议进行全外显子组测序和 15万例严重精神障碍患者的SNP阵列基因分型 控制。它将是大规模的，跨诊断的，基于临床精神病学中看到的患者，并且是全面的 分析超稀有外显子、稀有拷贝数和常见变异。因为化验成本太高了(开 8000万美元的订单)，我们正在与Regeneron基因组中心(RGC)合作，该中心将进行所有 基因组分析。NIMH的资金在每个地点50万美元的直接成本上限之内。 我们将：(1)获取临床上有严重精神障碍的样本。病例将被终生诊断为 精神分裂症(SCZ)、分裂情感障碍(SAD)、双相情感障碍(BD1)或严重抑郁症 精神障碍(SevMDD)。角色：UNC负责数据协调；采样点为ISMMS( 美洲和东亚)和加的夫(欧洲、非洲和南亚)，每个都将整理样本(即， MTAS、伦理批准、个人同意、协调表型、QC DNA)。第一阶段(1-2年)将重点 现有样本(N=10万例)。第二阶段(1-4年)将侧重于获取新样本(N=50K 病例)，并将使来自低收入国家的同事能够获得否则将是 不可能。这将帮助这些研究人员，并极大地增加基因组研究的多样性。2)基因组学 化验(1-4岁)。样本将从ISMMS和加的夫分批送往RGC。研资局将产生完整的 外显子组测序和SNP阵列数据。UNC和RGC将联合进行校准、QC、变体调用 (SNV、INDELS、SVS)和数组处理(常见SNP、推算和CNV)。QC包括评估 与独立数据集的多重偏差和比较。交付内容：针对Rare的分析就绪数据帧 外显子，罕见的CNV，和常见的遗传变异。3)对实质科学目的的分析。简而言之，主要的 分析主题是确定与以下方面有关的遗传变异：(A)严重精神疾病，(B)特定 (C)贯穿各领域的临床特征(例如，精神病、治疗抵抗、躁狂症、ID)。所有分析 将使用稳健的方法/偏差控制进行，与以前的相关研究进行正式比较，并进行评估 所有类型的可测量的跨不同基因祖先的遗传变异的影响。4)数据共享将 通过NIMH数据归档与NIMH政策保持一致。 这项拟议工作的成功完成将显著增加由 罕见的编码变异、罕见的CNV以及不太具体的GWA关联的负担-我们将显著 增加关于这些极其重要和负担沉重的疾病的遗传结构的知识。

Project Summary In this new and unfunded study, we will capitalize on the lessons from the past 15 years of psychiatric genomic. Based on these lessons, we propose an exceptionally novel and important set of aims to further knowledge of the genetic architecture of mental illness. We propose to perform whole-exome sequencing and SNP-array genotyping on >150,000 cases with severe psychiatric disorders along with a similar number of controls. It will be large, transdiagnostic, based on patients seen in clinical psychiatry, and comprehensively analyze ultra-rare exonic, rare copy number, and common variation. Because assay costs are prohibitive (on the order of $US 80 million), we are partnering with Regeneron Genomics Center (RGC) that will conduct all genomic assays. NIMH funding is within the $500K direct cost cap at each site. We will: (1) Acquire samples with clinically severe psychiatric disorders. Cases will have lifetime diagnoses of schizophrenia (SCZ), schizoaffective disorder (SAD), bipolar I disorder (BD1), or severe major depressive disorder (sevMDD). Roles: UNC is responsible for data coordination; the sampling sites are ISMMS (the Americas and East Asia) and Cardiff (Europe, Africa, and South Asia) and each will collate samples (i.e., MTAs, ethical approvals, individual consent, harmonize phenotypes, QC DNA). Phase 1 (Years 1-2) will focus on existing samples (N=100K cases). Phase 2 (Years 1-4) will focus on obtaining new samples (N=50K cases), and will enable colleagues from low-income countries to obtain genetic data that would otherwise be impossible. This will help those investigators and greatly increase diversity in genomics research. 2) Genomic assays (Years 1-4). Samples will be sent to RGC in batches from ISMMS and Cardiff. RGC will generate whole exome sequencing and SNP array data. UNC and RGC will jointly conduct alignment, QC, variant calling (SNVs, indels, SVs), and array processing (common SNPs, imputation and CNVs). QC includes assessment of multiple biases and comparison to independent datasets. Deliverable: analysis-ready data frames for rare exonic, rare CNV, and common genetic variation. 3) Analysis for substantive scientific aims. Briefly, the main analytical themes are to identify genetic variation associated with: (a) severe mental illness, (b) specific disorders, and (c) cross-cutting clinical features (e.g., psychosis, treatment resistance, mania, ID). All analyses will be conducted using robust methods/bias control, formally compared to relevant prior studies, and evaluate the impact of all types of measured genetic variation across diverse genetic ancestries. 4) Data sharing will align with NIMH policies via the NIMH Data Archive. Successful completion of the proposed work will markedly increase the number of genes pinpointed by burdens of rare coding variation, rare CNVs, as well as less specific GWAS associations–we will markedly increase knowledge of the genetic architectures of these critically important and burdensome disorders.