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

项目摘要 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， 对导致家族性主要疾病的突变的鉴定已经产生了非凡的生物学效应， 见解.然而，最近从罕见和常见变异分析中鉴定基因的成功表明， 该领域需要做什么来迎头赶上：扩大遗传研究的规模，多样性和范围。事实上， 认识到这一需要，发布了PAR-20-027，“在不同文化背景下精神障碍的遗传结构”， 人口”。为了响应这一呼吁，我们将创建精神疾病代表不足的人群 协会研究（PUMAS）项目，来自美国，南美洲的研究人员的国际合作 在拉丁美洲和非洲的大规模精神病遗传研究中， 人口，沿着几个领域的领导者在遗传数据的产生和分析。普玛斯会没事的 有能力发现精神分裂症和躁郁症的新基因;它将大大增加遗传多样性， 发现的努力，减少健康差距的重要一步;它将扩大精神病的范围， 通过对120，000个样本进行低通全基因组测序（我们将分析 加上我们团队已经测序的22，500个样本）。通过这些努力，我们还将发现 不同祖先间精神分裂症和双相情感障碍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， 来自非洲和来自美洲混合人群的双相情感障碍病例和对照， 通过招募17，000例新病例和16，500例匹配人群对照， 对照2)生成低通全基因组测序（WGS）数据和40，000例变异呼叫。 精神分裂症，40，000例双相情感障碍和40，000例来自非洲，美洲原住民和 混合祖先B）进行广泛的样品和变体质量控制。3)（一）系统分析 联合数据集为发现精神分裂症和双相情感障碍的遗传基础提供动力 和向下的等位基因频谱;和B）通过门户网站和浏览器，共享数据和结果的等位基因， 基因研究与世界PUMAS 120，000个样本WGS数据集，以及22，500个数据 先前测序的混合（AA+EA）样品，为遗传发现提供了足够的统计能力， SZ，BP，以及不同祖先的组合。我们的研究将确定新的基因和位点，增加 已知基因座精细定位的精确性，并形成多基因风险评分的基础知识库 (PRS)全球价值。

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.