2/3 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， 基因组的基于这些经验教训，我们提出了一套非常新颖和重要的目标， 了解精神疾病的遗传结构我们建议进行全外显子组测序， SNP-阵列基因分型在> 150，000例严重精神障碍患者中进行，沿着相似数量的 对照它将是大的，跨诊断的，基于临床精神病学中看到的患者， 分析超罕见外显子、罕见拷贝数和常见变异。由于分析成本过高（ 8000万美元），我们与Regeneron基因组学中心（RGC）合作， 基因组测定。NIMH的资金在每个站点的50万美元直接成本上限内。 我们将：（1）采集临床严重精神障碍患者的样本。病例的终身诊断为 精神分裂症（SCZ）、情感性精神障碍（SAD）、双相I型精神障碍（BD 1）或重度重度抑郁症 疾病（sevMDD）。作用：国家统计局负责数据协调;采样点是ISMMS（ 美洲和东亚）和卡迪夫（欧洲、非洲和南亚），每个国家都将整理样本（即， MTA、伦理批准、个人同意、协调表型、QC DNA）。第1阶段（1-2年）将侧重于 现有样本（N= 10万例）。第2阶段（第1-4年）将侧重于获得新样本（N= 50 K 这将使来自低收入国家的同事能够获得基因数据， 不可能的这将有助于这些研究人员，并大大增加基因组学研究的多样性。2)基因组 检测（1-4年级）。样本将分批从ISMMS和卡迪夫送往研究资助中心。研资局将提供 外显子组测序和SNP阵列数据。研究局和研资局将共同进行比对、质量控制、变异识别 (SNVs插入缺失、SV）和阵列处理（常见SNP、插补和CNV）。QC包括评估 多重偏差和与独立数据集的比较。可扩展：分析就绪数据帧，用于罕见 外显子、罕见CNV和常见遗传变异。3)为实质性科学目的进行分析。简而言之，主要 分析的主题是确定与以下因素相关的遗传变异：（a）严重精神疾病，（B）特异性 疾病，和（c）交叉临床特征（例如，精神病、治疗抵抗、躁狂症、ID）。所有分析 将使用稳健方法/偏倚控制进行，与相关既往研究进行正式比较，并评价 所有类型的测量的遗传变异在不同的遗传祖先的影响。4)数据共享将 通过NIMH数据档案与NIMH政策保持一致。 这项工作的成功完成将显著增加基因的数量， 罕见的编码变异，罕见的CNV，以及不太具体的GWAS关联的负担-我们将显着 增加对这些极其重要和负担沉重的疾病的遗传结构的了解。

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.