1/3 Genomics of Schizophrenia in the South African Xhosa

项目描述 这个国际合作项目的目标是响应PAR-20-027， 南非科萨人精神分裂症的结构。三个参与的网站有 已经成功地建立了必要的基础设施，以实现这一建议的目标。三 研究中心为华盛顿大学、西雅图大学（玛丽-克莱尔·金、杰克·麦克莱伦、汤姆·沃尔什、MPI）;哥伦比亚大学 纽约大学（专业研究员Ezra Susser）和南非开普敦大学（专业研究员Dan Stein）。 非洲人群比非洲以外的人群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。我们的初步研究（Gulsuner等人，科学，2020）是 第一次大规模的遗传研究精神分裂症的祖先非洲人口。我们发现科萨人 患有精神分裂症的个体（病例）在不耐受这种疾病的基因中富含罕见的破坏性突变。 突变。这种影响对于参与突触功能的基因中的破坏性突变尤其强烈。 这些结果扩展了对精神分裂症遗传学的理解，特别是支持寡基因严重 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，我们建议再招募1250例病例和1250例年龄和性别匹配的对照，所有 科萨语，使我们的研究总人数达到5425人。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型。的 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Illumina wg以识别常规类型的突变和（在具有突变的参与者的子集中， 现有的细胞系）长读PacBio wgs，以识别所有类型的结构变体，移动的转座 元素和重复扩展。此外，SAXv 2，非洲变异丰富的SNP阵列，开发用于 这个项目由Affysses，将用于识别拷贝数变异（CNVs）。 非洲是了解人类基因组和人类疾病信息量最大的大陆， 全球影响。非洲人群为筛查提供了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所有类型的破坏性突变，包括检测 特定病例的拷贝数变异和重复扩增，同时也为人类提供资源 全世界的基因组学研究。

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. The three sites are 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 (in a subset of participants with existing cell lines) 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.