2/3 Genomics of Schizophrenia in the South African Xhosa

2/3 南非科萨人精神分裂症的基因组学

• 批准号: 10598349
• 负责人: Ezra S. Susser
• 金额: $ 7.24万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598349
• 关键词: Africa; African; Age; Alleles; Binding; Blood; Brain; Cell Line; Code; Complex; Consent; Copy Number Polymorphism; Custom; DNA Transposable Elements; Detection; Diagnosis; Disease; Enhancers; Enrollment; Gender; Gene Mutation; Generations; Genes; Genetic; Genetic Variation; Genetic study; Genomic DNA; Genomics; Genotype; Goals; Grant; Human; Human Genetics; Human Genome; Human Resources; Individual; Infrastructure; International; Link; Location; Modeling; Modernization; Mutation; New York; Participant; Phase; Phenotype; Point Mutation; Population; Privatization; Protocols documentation; Recording of previous events; Regulatory Element; Research; Research Personnel; Role; SNP array; Sample Size; Sampling; Schizophrenia; Science; Signal Transduction; Site; South Africa; South African; Structure; Synapses; Technology; Testing; Universities; Untranslated RNA; Variant; Washington; base; case control; experience; genetic architecture; genome sequencing; human genomics; human reference genome; insertion/deletion mutation; international partnership; lymphoblast; novel; promoter; recruit; response; risk variant; screening; study population; synaptic function; transcription factor; whole genome

Contact PD/PI: Susser, Ezra S. PROJECT DESCRIPTION The goal of this international collaborative project, in response to PAR-20-027, is to characterize the genetic architecture of schizophrenia in the Xhosa population of South Africa. The three participating sites have already successfully established the infrastructure necessary to undertake the aims of this proposal: University of Washington, Seattle (Mary-Claire King, Jack McClellan, Tom Walsh, MPIs); Columbia University, New York (Ezra Susser, PI); and University of Cape Town, South Africa (Dan Stein, PI). African populations harbor far more genetic variation than out-of-Africa populations, facilitating discovery of associations between genotypes and phenotypes. Our initial study (Gulsuner at al., Science, 2020) was the first large-scale genetic study of schizophrenia in an ancestral African population. We discovered that Xhosa individuals with schizophrenia (cases) are enriched for rare damaging mutations in genes intolerant to such mutations. The effect was particularly strong for damaging mutations in genes involved in synaptic functioning. These results extend understanding of schizophrenia genetics, specifically supporting an oligogenic, severe alleles model and a role for rare damaging mutations in genes critical to synaptic signaling and plasticity. For this project, we propose to enroll an additional 1250 cases and 1250 age- and gender-matched controls, all Xhosa-speaking, bringing our total study population to 5425 participants. We will apply new genomic technology to identify previously undetectable classes of mutations likely to be implicated in schizophrenia. The genomic structure of Xhosa cases and controls will be characterized using whole genome sequencing (wgs), both short–read Illumina wgs to identify conventional classes of mutations and long-read PacBio wgs to identify structural variants of all types, mobile transposable elements, and repeat expansions. In addition, SAX v2, the African-variation-enriched SNP array developed for this project by Affymetrix, will be used to identify copy number variants (CNVs). Africa is the single most informative continent for understanding the human genome and human disorders with worldwide impact. African populations provide the most complete human reference genomes for screening candidate risk alleles for any phenotype. The whole-genome sequencing strategies used in this project allow the comparison of all classes of damaging mutations between cases and controls, including the detection of case-specific copy number variation and repeat expansions, while also providing a resource for human genomics research worldwide. Project Summary/Abstract Page 6

联系PD/PI：Susser，Ezra S. 项目描述 该国际合作项目的目标是响应于20-027帕尔（Par-027）的遗传学特征 南非XHOSA人口中精神分裂症的建筑。这三个参与网站有 已经成功建立了实现该提议目标所必需的基础设施：大学 华盛顿，西雅图（Mary-Claire King，Jack McClellan，Tom Walsh，MPIS）；纽约哥伦比亚大学 （Ezra Susser，pi）；和南非开普敦大学（Dan Stein，PI）。 非洲人口比非洲群体的遗传变异要多得多，支持发现 基因型与表型之间的关联。我们的初步研究（Al。的Gulsuner，Science，2020年）是 非洲祖先人口中精神分裂症的首次大规模遗传研究。我们发现xhosa 精神分裂症的个体（病例）富集了基因不耐受的罕见损害突变 突变。对于突触功能涉及的基因的破坏突变，这种效果尤其强。 这些结果扩展了对精神分裂症遗传学的了解，特别支持寡聚，严重的 等位基因模型和稀有损伤突变在对合成信号和可塑性至关重要的基因中的作用。 对于这个项目，我们建议将额外的1250例案件和1250个年龄和性别匹配的控件录入 说XHOSA，使我们的总研究人口达到5425名参与者。我们将应用新的基因组 识别可能在精神分裂症中实施的以前无法检测的突变类别的技术。 使用整个基因组测序（WGS），XHOSA病例和对照组的基因组结构将被表征 均简短阅读Illumina WGS，以识别传统类别的突变类别和长阅读PACBIO WGS以识别 各种类型的结构变体，移动转座元素和重复扩展。此外，萨克斯v2， Affymetrix为该项目开发的非洲变化添加的SNP阵列将用于识别副本 数字变体（CNV）。 非洲是理解人类基因组和人类疾病的最有用的大陆 全球影响。非洲人口提供了筛查最完整的人类参考基因组 任何表型的候选风险等位基因。该项目中使用的全基因组测序策略允许 比较病例和对照之间的所有损害突变类别的比较，包括检测 特定于案例的拷贝数变化和重复扩展，同时还为人类提供资源 全球基因组学研究。 项目摘要/摘要页面6