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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要最近的发现表明，特定的基因变异导致精神分裂症 (SZ) 的风险极高，这是一种除了这些基因发现之外，在精神综合征方面也取得了同步进展。分子神经科学，包括诱导多能干（iPS）细胞技术；高内涵成像和单细胞基因组学等技术；以及多重“细胞村”方法。这些技术允许对先前的复杂生物过程进行严格有效的询问遗传发现和技术进步的结合是难以接近的人类神经细胞类型。解决现代精神病学“大白鲸”问题的强大工具：什么是引起 SZ 表型的潜在病理生理学是什么？我们认为罕见 SZ 的高外显率突变源自分子和细胞水平的巨大影响，我们将确定下游目标并进行研究。五种罕见的 SZ 相关变异影响的途径具有较大的效应：染色体缺失位置 2p16（位于 NRXN1 基因）、3q29、15q13.3、22q11.2 和 16p11 处的重复是一个关键优势。该提案的重点是我们进入基因组精神病学队列 (GPC)。重要的是，GPC 是一个多元化的队列。我们将选择具有显着非洲血统的样本进行研究。来自携带这五种定义变异之一的 SZ 个体的淋巴细胞（每种基因型 n = 20），优先考虑代表性不足的少数群体，以产生 iPS 细胞系。 GPC 的一个明显优势是其规模大。多样化的对照样本，使我们能够选择与 SZ 的基因组背景相匹配的对照 (n=40) 对这些与 SZ 相关的罕见病例进行了一致但令人惊讶的观察。变异是它们在效应大小和表型特征上的相似性，从而产生了这样的假设：这些变异集中在下游分子靶标和/或细胞途径上，我们将检验这一假设。 SZ 相关的罕见突变会导致神经元染色质水平的分子扰动可及性和基因表达，以及受其中两个或多个 SZ 相关的基因或途径的影响最后，我们将验证分子途径。使用多模式细胞表型水平分析来识别特定的生物过程。被 SZ 相关位点破坏将为了解这种疾病的复杂分子生物学打开一扇窗户。我们的机制研究的基础将包括具有不同遗传背景的受试者历史上在遗传学研究中代表性不足，确保我们的结果可以推广到这些社区，本文生成的工具和数据将遭受不成比例的不良心理健康后果的影响。支持心理健康领域与 NIMH 的优先事项保持一致，带来对神经生物学的变革性见解 SZ 的研究，并发现可能成为治疗发现的启动点的新靶点。