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: 10322738
• 负责人: Ezra S. Susser
• 金额: $ 44.38万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322738
• 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

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.

项目描述 为了响应 PAR-20-027，这个国际合作项目的目标是表征遗传 南非科萨人精神分裂症的结构。三个参与站点有 已经成功建立了实现本提案目标所需的基础设施：大学 华盛顿西雅图（Mary-Claire King、Jack McClellan、Tom Walsh、MPI）；纽约哥伦比亚大学 （埃兹拉·苏瑟，PI）；和南非开普敦大学（Dan Stein，PI）。 非洲人口比非洲以外的人口拥有更多的遗传变异，这有助于发现 基因型和表型之间的关联。我们最初的研究（Gulsuner at al., Science, 2020）是 首次对非洲祖先群体的精神分裂症进行大规模遗传学研究。我们发现科萨语 精神分裂症患者（病例）富含不耐受这种疾病的基因中罕见的破坏性突变 突变。对于涉及突触功能的基因的破坏性突变，这种效应尤其强烈。 这些结果扩展了对精神分裂症遗传学的理解，特别支持寡基因、严重的 等位基因模型以及对突触信号传导和可塑性至关重要的基因中罕见的破坏性突变的作用。 对于这个项目，我们建议额外招募 1250 个病例和 1250 个年龄和性别匹配的对照，所有 讲科萨语，使我们的研究总人数达到 5425 名参与者。我们将应用新的基因组 技术来识别以前无法检测到的可能与精神分裂症有关的突变类别。这 将使用全基因组测序（wgs）来表征科萨病例和对照的基因组结构， 短读长 Illumina 工作组用于识别常规突变类别，长读长 PacBio 工作组用于识别 所有类型的结构变体、移动转座元件和重复扩展。此外，SAX v2 Affymetrix 为本项目开发的富含非洲变异的 SNP 阵列将用于识别拷贝 数字变体 (CNV)。 非洲是了解人类基因组和人类疾病信息最丰富的大陆 全球影响。非洲人群提供最完整的人类参考基因组用于筛选 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 病例和对照之间所有类别的破坏性突变的比较，包括检测 特定病例的拷贝数变异和重复扩展，同时也为人类提供资源 全球基因组学研究。