1/3 Sequencing and Trans-Diagnostic Phenotyping of Severe Mental Illness in Diverse Populations

不同人群中严重精神疾病的 1/3 测序和跨诊断表型

基本信息

批准号：
10502677
负责人：
PATRICK F SULLIVAN
金额：
$ 75.87万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/10502677
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

项目摘要

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.

项目概要在这项新的、无资助的研究中，我们将利用过去 15 年精神病学的经验教训基于这些经验教训，我们提出了一套极其新颖且重要的目标来进一步推进。我们建议进行全外显子组测序并了解精神疾病的遗传结构。对超过 150,000 例患有严重精神疾病以及类似数量的病例进行 SNP 阵列基因分型它将是大规模的、跨诊断的、基于临床精神病学的患者的、全面的。分析超罕见的外显子、罕见的拷贝数和常见的变异，因为检测成本过高（上。 8000 万美元），我们正在与再生元基因组中心 (RGC) 合作，该中心将开展所有 NIMH 资助的每个站点的直接成本上限为 50 万美元。我们将： (1) 获取患有临床严重精神疾病的样本病例将进行终生诊断。精神分裂症 (SCZ)、分裂情感性障碍 (SAD)、I 型双相情感障碍 (BD1) 或严重抑郁症角色：UNC 负责数据协调；采样点是 ISMMS（ISMMS）。美洲和东亚）和卡迪夫（欧洲、非洲和南亚），每个地区都会核对样本（即，第 1 阶段（第 1-2 年）将重点关注 MTA、道德批准、个人同意、协调表型、QC DNA。第 2 阶段（第 1-4 年）将侧重于获取新样本（N=50K）。例），并使来自低收入国家的同事能够获得原本会被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。检测（第 1-4 年）。样品将从 ISMMS 分批发送至 RGC，RGC 将生成完整样品。 UNC和RGC将联合进行外显子组测序和SNP阵列数据比对、QC、变异识别。（SNV、插入缺失、SV）和阵列处理（常见 SNP、插补和 QC 包括评估）。多重偏差以及与独立数据集的比较：可用于分析的稀有数据框架。外显子、罕见CNV和常见遗传变异 3) 实质性科学目的分析。分析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) 特定疾病疾病，以及 (c) 交叉临床特征（例如精神病、治疗抵抗、躁狂、智力障碍）。将使用稳健的方法/偏差控制进行，与相关的先前研究进行正式比较，并评估不同遗传祖先的所有类型的测量遗传变异的影响 4) 数据共享。通过 NIMH 数据档案与 NIMH 政策保持一致。成功完成拟议的工作将显着增加由罕见编码变异、罕见 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且繁重的疾病的遗传结构的了解。