3/4 Powering Genetic Discovery for Severe Mental Illness in Latin American andAfrican Ancestries

3/4 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: 10473124
• 负责人: MICHELE T PATO
• 金额: $ 58.77万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473124
• 关键词: Abbreviations; Africa; African; 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; Hispanics; Individual; International; Interview; Latin American; Latino; 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; Research Personnel; Sample Size; Sampling; Sampling Studies; Schizoaffective Disorders; Schizophrenia; Severities; Single Nucleotide Polymorphism; South Africa; South America; Structure; 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.

项目摘要 精神分裂症和躁郁症的基因发现在其他医学领域的落后 识别负责家庭形式的主要疾病的突变已产生非凡的生物学 见解。但是，稀有和常见变体分析的基因鉴定的最新成功表明 该领域需要采取的措施来赶上：扩大遗传研究的规模，多样性和范围。确实，尼姆 认识到这一需求，并发布了Par-20-027，“祖先多样化的精神障碍遗传结构 人口。“为了回应这个电话，我们将创造出精神疾病中人群不足的人群 协会研究（PUMAS）项目，美国，南美的研究人员的国际合作 和非洲的大规模精神病研究在拉丁裔和非洲的良好记录 人口，以及该领域的几个遗传数据生成和分析领导者。彪马会很好 有动力发现精神分裂症和双相情感障碍的新基因；它将大大增加通用的多样性 发现工作，这是迈向减少健康分配的重要一步；它将扩大精神病的范围 通过为120,000个样品生成低通的整个基因组测序，基因组学（我们将分析 我们的团队已经对22,500个样本进行了测序。通过这些努力，我们还将发现 在潜水祖先和 环境。 PUMAS项目的目的是：1）建立精神分裂症病例的PUMAS样本库， 来自非洲的双极案件和对照，来自美洲的混合人群，获得了总样本 通过招募17,000个新案件和16,500个 控件。 2）生成低通的全基因组测序（WGS）数据，并在40,000例 精神分裂症，40,000例躁郁症和40,000例来自非洲，美洲原住民和 混合的祖先b）执行广泛的样本和变体质量控制。 3）a）系统分析 将数据集的结合到能力发现精神分裂症的遗传基础和跨多个祖先的双相 并下降等位基因频谱； b）通过门户和浏览器，共享 与世界的遗传研究。 PUMA 120,000样品WGS数据集，以及22,500的数据 先前测序的混合（AA+EA）样本，为遗传发现提供了足够的统计能力 SZ，BP和在潜水员祖先之间合并。我们的研究将确定新基因和局部，增加 已知局部精细映射的精确图，并构成多基因风险评分的基础知识基础 全球价值的（PR）。