1/4 Powering Genetic Discovery for Severe Mental Illness in Latin American and African 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，在其他领域 重大疾病家族性形式的突变鉴定产生了非同寻常的生物学结果 洞察力。然而，最近从罕见和常见的变异分析中获得的基因鉴定的成功表明 该领域需要做的是迎头赶上：扩大基因研究的规模、多样性和范围。的确，NIMH 认识到这一需求，发布了PAR-20-027《祖先多样性精神障碍的遗传结构》 人口数量。“响应这一号召，我们将创造精神疾病中代表性不足的人群 协会研究(Pumas)项目，来自美国、南美的研究人员的国际合作 以及在拉丁裔和非洲人进行大规模精神遗传学研究方面记录最好的非洲 以及该领域在基因数据生成和分析方面的几位领先者。美洲狮会好起来的 有能力发现精神分裂症和躁郁症的新基因；它将显著增加基因的多样性 发现努力，这是减少健康差距的重要一步；它将扩大精神病学的范围 通过为120,000个样本生成低通全基因组测序来实现基因组学(我们将对此进行分析 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 精神分裂症和双相情感障碍的遗传结构在不同祖先和不同人群中的异同 环境。美洲狮项目的目标是：1)建立美洲狮精神分裂症病例样本库， 来自非洲和美洲混血人群的双相病例和对照，实现了总样本 在183 500例(88 600例病例和94 900例匹配人口对照)中招募17 000例新病例和16 500例 控制。2)生成低通全基因组测序(WGS)数据和对40,000个病例的变体调用 精神分裂症，40,000例双相情感障碍患者和40,000名来自非洲、美洲原住民和 混合的祖先b)执行广泛的样品和变化的质量控制。3)a)系统分析 组合数据集支持跨不同祖先发现精神分裂症和双相情感障碍的遗传基础 以及b)通过门户和浏览器，共享数据和结果 与世界共同进行基因研究。美洲狮120,000个样本WGS数据集，以及22,500个数据 以前测序的混合(AA EA)样本，为基因发现提供了足够的统计能力 SZ、BP和跨不同祖先的组合。我们的研究将发现新的基因和基因座，增加 已知基因座精细定位的精确度，并形成多基因风险评分的基础知识库 (Prs)具有全球价值。

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.