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

不同人群中严重精神疾病的 3/3 测序和跨诊断表型

• 批准号: 10502341
• 负责人: Valentina Escott-Price
• 金额: $ 52.91万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502341
• 关键词: Africa; Americas; Asia; Biological Assay; Bipolar I; Clinical; Code; Collaborations; Consent; Contracts; DNA; Data; Data Set; Deposition; Development; Diagnosis; Diagnostic; Direct Costs; Disease; Ethics; Etiology; Europe; Far East; Funding; Genes; Genetic; Genetic Variation; Genomics; Genotype; Human; Individual; Knowledge; Major Depressive Disorder; Manic; Measures; Mental disorders; Meta-Analysis; Methods; Moon; National Institute of Mental Health; Occupations; Output; Paper; Patients; Phase; Phenotype; Policies; Population Heterogeneity; Process; Psychiatry; Psychoses; Research; Research Personnel; Resource Sharing; Role; SNP array; Sample Size; Sampling; Schizoaffective Disorders; Schizophrenia; Science; Severities; Site; Technology; Therapeutic; Training; Trans-Omics for Precision Medicine; Travel; Variant; Work; base; cost; data archive; data sharing; exome; exome sequencing; gene discovery; genetic architecture; genome wide association study; genomic variation; insertion/deletion mutation; low income country; mortality risk; novel; novel therapeutics; programs; psychiatric genomics; risk variant; secondary analysis; severe mental illness; severe psychiatric disorder; therapy resistant

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.

项目摘要 在这项新的无资助的研究中，我们将利用过去15年的精神病学课程 基因组。基于这些课程，我们提出了一套非常新颖且重要的目标，以进一步 了解精神疾病的遗传结构。我们建议执行全外观测序和 SNP阵列基因分型> 150,000例患有严重精神疾病的病例以及类似数量的 控件。根据临床精神病学中看到的患者，它将很大，经诊断，并全面 分析超稀有外显子，稀有拷贝数和常见变化。因为禁止测定费用（on 我们正在与Regeneron Genomics Center（RGC）合作，该订单为8000万美元） 基因组测定。 NIMH资金在每个站点的50万美元直接成本上限范围内。 我们将：（1）获取患有临床严重精神疾病的样本。病例将终身诊断 精神分裂症（SCZ），精神分裂症（SAD），双相情感障碍（BD1）或严重的主要抑郁症 疾病（SEVMDD）。角色：UNC负责数据协调；采样站点是ISMM（ 美洲和东亚）和加的夫（欧洲，非洲和南亚），每个人都将整理样本（即 MTA，道德批准，个人同意，协调表型，QC DNA）。阶段1（1 - 2年）将集中精力 在现有样品中（n = 100K案例）。第2阶段（1-4年）将重点放在获得新样本（n = 50k） 案例），并将使低收入国家的同事获得遗传数据，否则 不可能的。这将有助于这些研究者，并大大增加基因组学研究的多样性。 2）基因组 测定（1 - 4年）。样本将分批从ISMMS和Cardiff发送到RGC。 RGC将产生整体 外显子测序和SNP数组数据。 UNC和RGC将共同执行QC，变体呼叫 （SNV，Indels，SVS）和数组处理（常见的SNP，插补和CNV）。 QC包括评估 多个偏见和与独立数据集的比较。可交付：稀有分析的数据帧 外显子，罕见的CNV和常见的遗传变异。 3）分析实质性科学目的。简而言之，主 分析主题是确定与：（a）严重精神疾病相关的遗传变异，（b）特定的 疾病和（c）横切临床特征（例如，精神病，治疗性，躁狂症，ID）。所有分析 将使用可靠的方法/偏见控制进行，并正式与相关的先前研究进行比较，并评估 在潜水员遗传祖先之间所有类型的测量遗传变异的影响。 4）数据共享将 通过NIMH数据存档与NIMH策略保持一致。 拟议工作的成功完成将显着增加基因的数量。 稀有编码变化，稀有CNV以及较少特定的GWAS关联的Burnens - 我们将明显 增加对这些非常重要和朴素疾病的遗传体系结构的了解。