Cellular consequences and convergent biology of schizophrenia-associated rare variants in the diverse GPC cohort

不同 GPC 队列中精神分裂症相关罕见变异的细胞后果和趋同生物学

• 批准号: 10672460
• 负责人: RONALD P HART
• 金额: $ 125.55万
• 依托单位: RUTGERS BIOMEDICAL AND 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 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672460
• 关键词: 22q11; 22q11.2; 3q29; ATAC-seq; Address; Affect; African ancestry; Biological Assay; Biological Process; Biology; Cell Line; Cell Nucleus; Cell physiology; Cells; Characteristics; Chromatin; Clinical assessments; Communities; Complex; Confounding Factors (Epidemiology); Copy Number Polymorphism; Cryopreservation; Data; Delphinapterus leucas; Disease; Ectopic Expression; Ensure; Functional disorder; Gene Expression; Genes; Genetic; Genetic study; Genomics; Genotype; Glutamates; Human; Image; Individual; Investigation; Lead; Location; Lymphocyte; Mental Health; Mental disorders; Modernization; Molecular; Molecular Biology; Molecular Target; Mutation; National Institute of Mental Health; Neurobiology; Neurons; Neurosciences; Outcome; Participant; Pathway interactions; Penetrance; Phenotype; Physiology; Protocols documentation; Psychiatric Diagnosis; Psychiatry; Psychoses; Sampling; Schizophrenia; Synapses; Synaptic Transmission; Syndrome; Techniques; Technology; Testing; Therapeutic; Time; Underrepresented Minority; Variant; Work; cell type; chromosomal location; cohort; excitatory neuron; gamma-Aminobutyric Acid; genetic variant; genomic data; high risk; induced pluripotent stem cell; induced pluripotent stem cell technology; inhibitory neuron; insight; mitochondrial dysfunction; molecular phenotype; multimodality; multiple omics; neuronal excitability; novel; psychogenetics; rare variant; schizophrenia risk; sensor; stem cell biology; tool; transcriptome sequencing

Project Summary / Abstract Recent discoveries implicate specific genetic variants that confer extremely high risk for schizophrenia (SZ), a devastating psychiatric syndrome. Alongside these genetic discoveries there have been parallel advances in molecular neuroscience, including induced pluripotent stem (iPS) cell technology; high-throughput cellular technologies such as high content imaging and single cell genomics; and multiplex “cell village” approaches. These techniques allow for rigorous yet efficient interrogation of complex biological processes in previously inaccessible human neuronal cell types. The combination of genetic findings and technological advances are powerful tools for addressing what has become the “great white whale” of modern psychiatry: What is the underlying pathophysiology that gives rise to a SZ phenotype? We propose that high penetrance of rare SZ mutations derive from large effects at the molecular and cellular levels. We will identify downstream targets and pathways impacted by five rare SZ-associated variants with large effect sizes: deletions at chromosomal locations 2p16 (localized to the NRXN1 gene), 3q29, 15q13.3, 22q11.2, and duplication at 16p11. A key strength of this proposal is our access to the Genomic Psychiatry Cohort (GPC). Importantly, the GPC is a diverse cohort with significant representation of African ancestry. We will select for study previously-banked cryopreserved lymphocytes from individuals with SZ who carry one of these five defined variants (n=20 each genotype), prioritizing underrepresented minorities, to generate iPS cell lines. A clear advantage of the GPC is its large diverse control sample, allowing us to select controls (n=40) that are matched by genomic background to the SZ cases, increasing the rigor of our study. A consistent but surprising observation about these SZ-associated rare variants is their similarity in both effect size and phenotypic characteristics, giving rise to the hypothesis that these variants converge on downstream molecular targets and/or cellular pathways. We will test the hypothesis that SZ-associated rare mutations cause molecular perturbations in neurons at the level of chromatin accessibility and gene expression and that genes or pathways impacted by two or more of these SZ-associated variants converge, with more overlap than expected by chance. Finally, we will validate molecular pathways using multimodal cellular phenotypic levels of analysis. Identifying the specific biological processes that are disrupted by SZ-associated loci will open a window into the complex molecular biology of this disorder. The substrate for our mechanistic studies will include subjects with diverse genetic backgrounds that have been historically underrepresented in genetic studies, ensuring that our results are generalizable to these communities, who suffer disproportionately from adverse mental health outcomes. The tools and data generated herein will support the mental health field aligning with NIMH priorities, lead to transformative insights into the neurobiology of SZ, and uncover novel targets that may be a launch point for therapeutic discovery.

项目摘要 /摘要 最近的发现暗示了特定的遗传变异，即精神分裂症（SZ）极高的风险，A 毁灭性的精神综合症。除了这些遗传发现， 分子神经科学，包括诱导多能茎（IPS）细胞技术；高通量细胞 高含量成像和单细胞基因组学之类的技术；和多重“牢房村”的方法。 这些技术允许对以前的复杂生物学过程进行严格但有效的询问 无法访问的人类神经元细胞类型。遗传发现和技术进步的结合是 解决现代精神病学“大白鲸”的强大工具：什么是 产生SZ表型的基本病理生理学？我们建议稀有SZ的高渗透率 突变来自分子和细胞水平的大作用。我们将确定下游目标， 受五个稀有SZ相关的变体影响的途径大小较大：染色体上的缺失 位置2P16（位于NRXN1基因的位置），3Q29，15Q13.3，22Q11.2，在16p11中进行了复制。关键力量 这项建议是我们进入基因组精神病学队列（GPC）的访问权限。重要的是，GPC是潜水员队列 具有非洲血统的大量代表。我们将选择先前保存的研究 来自SZ个体的淋巴细胞，携带这五个定义变体之一（n = 20个基因型）之一， 优先考虑代表性不足的少数族裔，以生成IPS细胞系。 GPC的明显优势是它的大 不同的控制样本，使我们能够选择由基因组背景匹配的对照（n = 40） 案例，增加了我们研究的严格性。对这些SZ相关的罕见的一致但令人惊讶的观察 变体是它们在效应大小和表型特征上的相似性，这引起了以下假设。 这些变体会在下游分子靶标和/或细胞途径上收敛。我们将检验假设 SZ相关的稀有突变引起染色质水平的神经元的分子扰动 可访问性和基因表达以及受这些SZ相关的两个或多个影响的基因或途径 变体融合，重叠比偶然的预期更多。最后，我们将验证分子途径 使用多模式的细胞表型分析水平。确定特定的生物学过程 与SZ相关的基因座破坏将为该疾病的复杂分子生物学打开一个窗口。这 我们的机械研究的基材将包括具有潜水员遗传背景的受试者 从历史上看 因不利的心理健康结果而遭受不成比例的人。本文生成的工具和数据将 支持与NIMH优先级保持一致的心理健康领域，导致对神经生物学的变革见解 SZ和发现的新颖目标，这可能是治疗发现的发射点。