1/3 Genomics of Schizophrenia in the South African Xhosa

项目说明 这一国际合作项目的目标是响应PAR-20-027，描述基因的特征 南非科萨族人群中精神分裂症的架构。这三个参与网站有 已经成功地建立了实现本提案目标所需的基础设施。三位一体 网站是华盛顿大学西雅图分校(Mary-Claire King，Jack McClellan，Tom Walsh，MPIS)；哥伦比亚 纽约大学(Ezra Susser，PI)；南非开普敦大学(Dan Stein，PI)。 非洲人比非洲以外的人拥有更多的基因变异，这有助于发现 基因型别和表型型别之间的关联。我们最初的研究(Gulsuner at al.，Science，2020)是 首次对非洲祖先人群中的精神分裂症进行大规模遗传学研究。我们发现科萨 精神分裂症患者(病例)在不耐受此类疾病的基因中发现罕见的破坏性突变。 突变。对于涉及突触功能的基因的破坏性突变，这种影响尤其强烈。 这些结果扩展了对精神分裂症遗传学的理解，特别是支持一种少基因重症 等位基因模型和对突触信号和可塑性至关重要的基因罕见破坏性突变的作用。 对于这个项目，我们建议再招募1250个病例和1250个年龄和性别匹配的对照，全部 科萨-我是科萨，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 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的技术。这个 科萨病患者和对照的基因组结构将使用全基因组测序(WGS)来表征， 既有短读Illumina WGS来识别传统类型的突变，也有(在参与者的子集中) 现有细胞系)长阅读PacBio WGS以识别所有类型的结构变体，可移动转座 元素，并重复展开。此外，SAX v2，非洲变异丰富的SNP阵列为 该项目由Affymetrix完成，将用于识别拷贝数变异(CNV)。 非洲是了解人类基因组和人类疾病的唯一信息量最大的大陆 世界性的影响。非洲人口为筛选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 病例和对照之间所有种类的破坏性突变的比较，包括检测 特定于案例的拷贝数变化和重复扩展，同时也为人类提供了资源 全球基因组学研究。

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.