4/4 Powering Genetic Discovery for Severe Mental Illness in Latin American and African Ancestries

4/4 推动拉丁美洲和非洲血统中严重精神疾病的基因发现

• 批准号: 10478253
• 负责人: NELSON B. FREIMER
• 金额: $ 127.94万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10478253
• 关键词: Abbreviations; Africa; African; African ancestry; Americas; Area; Biological; Bipolar Disorder; Code; Collaborations; Collection; Computerized Medical Record; Copy Number Polymorphism; Data; Data Set; Diagnostic; Disease; Environment; Equilibrium; European; Foundations; Gene Frequency; Generations; Genes; Genetic; Genetic Research; Genetic Variation; Genetic study; Genomics; Genotype; Individual; International; Interview; Latin American; Latino; Latino Population; Learning; Letters; Linkage Disequilibrium; Medicine; Mental disorders; Meta-Analysis; Mood Disorders; Mutation; National Institute of Mental Health; Native American Ancestry; Native Americans; Patients; Phenotype; Population; Population Control; Population Heterogeneity; Principal Component Analysis; Psychiatry; Psychoses; Psychotic Disorders; Quality Control; Questionnaires; Reduce health disparities; Research Personnel; Sample Size; Sampling; Sampling Studies; Schizoaffective Disorders; Schizophrenia; Severities; Single Nucleotide Polymorphism; South Africa; South America; Underrepresented Populations; Variant; bipolar patients; care outcomes; case control; cohort; data sharing; exome; exome sequencing; genetic architecture; genome sequencing; genomic locus; health disparity; insight; knowledge base; neuropsychiatry; polygenic risk score; psychiatric genomics; psychogenetics; rare variant; recruit; response; risk variant; screening; severe mental illness; study population; success; variant detection; whole genome

Project Summary Genetic discovery for schizophrenia and bipolar disorder lags behind that in other areas of medicine, where the identification of mutations responsible for familial forms of major disorders has yielded extraordinary biological insights. However, recent successes in gene identification from both rare and common variant analyses indicate what the field needs to do to catch up: expand the size, diversity and scope of genetic studies. Indeed, NIMH recognized this need, issuing PAR-20-027, “Genetic Architecture of Mental Disorders in Ancestrally Diverse Populations.” In response to this call, we will create the Populations Underrepresented in Mental illness Association Studies (PUMAS) Project, an international collaboration of investigators from the US, South America and Africa with the strongest track record of large-scale psychiatric genetic research in Latino and African populations, along with several of the field’s leaders in genetic data generation and analysis. PUMAS will be well powered to discover new genes for schizophrenia and bipolar; it will dramatically increase the diversity of genetic discovery efforts, an important step towards reducing health disparities; and it will expand the scope of psychiatric genomics by generating low-pass whole genome sequencing for 120,000 samples (which we will analyze together with 22,500 samples already sequenced by our team). Through these efforts we will also discover similarities and differences in genetic architecture of schizophrenia and bipolar across diverse ancestries and environments. The Aims of the PUMAS project are to: 1) Build the PUMAS sample bank of schizophrenia cases, bipolar cases and controls from Africa and from admixed populations in the Americas, achieving a total sample of 183,500 (88,600 cases and 94,900 matched population controls) by recruiting 17,000 new cases and 16,500 controls. 2) Generate low-pass whole genome sequencing (WGS) data and variant calls on 40,000 cases of schizophrenia, 40,000 cases of bipolar disorder and 40,000 matched controls from African, Native American and admixed ancestries b) perform extensive sample and variant quality control. 3) a) Systematically analyze the combined dataset to power discovery of the genetic basis of schizophrenia and bipolar across diverse ancestries and down the allele frequency spectrum; and b) through portals and browsers, share the data and results of the genetic studies with the world. The PUMAS 120,000 sample WGS dataset, together with data for 22,500 previously sequenced admixed (AA+EA) samples, provides sufficient statistical power for genetic discovery for SZ, BP, and combined across diverse ancestries. Our study will identify new genes and loci, increase the precision of fine-mapping of known loci, and form the foundational knowledge base for polygenic risk scores (PRS) of global value.

项目概要 精神分裂症和双相情感障碍的基因发现落后于其他医学领域，其中 鉴定导致重大疾病家族形式的突变已经产生了非凡的生物学成果 见解。然而，最近通过罕见和常见变异分析进行基因鉴定的成功表明 该领域需要做些什么才能迎头赶上：扩大遗传学研究的规模、多样性和范围。事实上，美国国家精神卫生研究所 认识到这一需求，发布了 PAR-20-027，“祖先多样化的精神障碍的遗传结构” 人口。”为了响应这一号召，我们将创建精神疾病代表性不足的人群 关联研究 (PUMAS) 项目，来自美国、南美洲的研究人员的国际合作 拉丁美洲和非洲在大规模精神病学基因研究方面拥有最强的记录 人口，以及遗传数据生成和分析领域的几位领导者。彪马会好起来的 有能力发现精神分裂症和双相情感障碍的新基因；它将极大地增加遗传的多样性 发现工作，是缩小健康差距的重要一步；它将扩大精神科的范围 基因组学，通过对 120,000 个样本（我们将对其进行分析）生成低通全基因组测序 以及我们团队已测序的 22,500 个样本）。通过这些努力我们还将发现 不同祖先的精神分裂症和躁郁症遗传结构的相似性和差异 环境。 PUMAS 项目的目标是： 1) 建立 PUMAS 精神分裂症病例样本库， 来自非洲和美洲混合人群的躁郁症病例和对照，获得了总样本 通过招募 17,000 个新病例和 16,500 个病例，共 183,500 个病例（88,600 个病例和 94,900 个匹配的人群对照） 控制。 2) 生成 40,000 个病例的低通全基因组测序 (WGS) 数据和变异调用 精神分裂症、40,000 例双相情感障碍病例和 40,000 例来自非洲、美洲原住民和 混合血统 b) 进行广泛的样本和变异质量控制。 3) a) 系统分析 组合数据集有助于发现不同祖先的精神分裂症和双相情感障碍的遗传基础 并降低等位基因频谱； b) 通过门户网站和浏览器共享数据和结果 与世界进行遗传学研究。 PUMAS 120,000 个样本 WGS 数据集，以及 22,500 个样本的数据 先前测序的混合 (AA+EA) 样本，为基因发现提供了足够的统计能力 SZ、BP 以及不同血统的结合。我们的研究将识别新的基因和位点，增加 已知位点精细定位的精度，并形成多基因风险评分的基础知识库 (PRS) 具有全球价值。