1/3-Schizophrenia Genetics and Brain Somatic Mosaicism

1/3-精神分裂症遗传学和脑体细胞​​镶嵌

• 批准号: 9766879
• 负责人: Daniel Weinberger
• 金额: $ 69.62万
• 依托单位: LIEBER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-20 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766879
• 关键词: Adult; Affect; Autopsy; Brain; Brain region; Cell Nucleus; Cell model; Cells; Cerebellum; Characteristics; Clinical; Collaborations; Copy Number Polymorphism; Cultured Cells; DNA; DNA Sequence; DNA analysis; DNA sequencing; Data; Defect; Diagnosis; Disease; Elements; Engineering; Etiology; Event; Exhibits; Expression Profiling; Family; Fibroblasts; Frequencies; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Structures; Genetic Variation; Genome; Genomic DNA; Genomic Instability; Genomics; Goals; Hallucinations; Hippocampus (Brain); Human; Human Genetics; Impaired cognition; Impairment; Incidence; Individual; Inherited; Lead; Location; Molecular; Mosaicism; Mutation; Neurites; Neurobiology; Neuroglia; Neurology; Neurons; Nucleotides; Paranoia; Pathogenesis; Pathogenicity; Patients; Pattern; Population; Process; Psychiatry; Public Health; RNA analysis; Research; Research Personnel; Retrotransposition; Retrotransposon; Sampling; Schizophrenia; Somatic Mutation; Structure; Symptoms; Techniques; Testing; Tissues; Validation; Variant; base; brain tissue; cell type; demographics; experimental study; frontal lobe; genetic architecture; genetic variant; genome sequencing; genome wide association study; genomic variation; gray matter; human embryonic stem cell; human genomics; improved; mouse model; neuropsychiatric disorder; new therapeutic target; progenitor; programs; public health relevance; risk variant; single cell analysis; tool; transcriptome; transcriptome sequencing; whole genome

 DESCRIPTION (provided by applicant): Schizophrenia (SCZD) is a debilitating and typically incurable neuropsychiatric disease that affects 1% of the human population. Disease symptoms, which include hallucinations, paranoia, and impaired cognition, are thought to arise from impairments in neuronal connectivity and plasticity, but etiology of these defects remains unclear. Multiple lines of evidence suggest a strong genetic component to SCZD. Thus, identifying genetic variants associated with SCZD may provide critical tools for understanding and treating the disease. Indeed, recent genome wide association studies have identified >100 loci that are associated with SCZD, but these genetic variants account for only a small percentage of disease incidence. One potential explanation for this unsatisfying result is that SCZD risk alleles are not inherited through the germline, but instead arise through somatic mutations within neurons of affected individuals. Perhaps it is the propensity for somatic mosaicism that is inherited in patients with SCZD. It is now clear that somatic mosaicism of DNA sequence is much more common than previously thought (i.e., all cells within an individual do not contain the same genome), and that this phenomenon is particularly prevalent in the brain. These genomic differences may contribute to the diversity of neuronal function. However, dysregulation of processes that generate or control somatic mosaicism may lead to disease-related genomic instability. Our hypothesis, therefore, is that somatic mosaicism in neurons or their progenitors are a major contributor to SCZD pathogenesis. Aim 1 will use single-cell genomic sequencing techniques to identify somatic copy number variants (CNVs) in neuronal and non-neuronal cell types from patients with SCZD or neurotypic controls. These analyses will focus on the frontal cortex and hippocampus, two brain regions associated with SCZD pathogenesis. Results will determine whether somatic CNVs are overrepresented in SCZD brains, and whether SCZD risk alleles are disproportionately affected by these CNVs. Aim 2 will characterize somatic retrotransposon insertions within these same cell types, asking whether the frequency or location of retrotransposition events is altered in neurons from patients with SCZD compared with controls. A total of 8000 neurons will be analyzed in Aims 1 and 2, making this the most comprehensive analysis of neuronal somatic mosaicism to date. In Aim 3, genomic variants most overrepresented in patients with SCZD (identified in Aims 1 and 2) will be engineered into hESCs for functional validation tests. It has been shown that cultured neurons derived from patients with SCZD exhibit reduced levels of connectivity and have underdeveloped neurites compared with controls. Similar analyses will be performed using isogenic and mosaic cultures of neurons derived from engineered hESCs. Results from these studies will determine whether the level, pattern, or type of somatic mosaicism is altered in SCZD neurons, and potentially identify genes and gene networks most affected by these changes. Identifying causal disease factors will provide new therapeutic targets and move us closer to finding a cure for this devastating disease.

 描述（由申请人提供）：精神分裂症 (SCZD) 是一种使人衰弱且通常无法治愈的神经精神疾病，影响着 1% 的人口。疾病症状，包括幻觉、偏执和认知受损，被认为是由神经元连接性和可塑性受损引起的，但这些缺陷的病因仍不清楚。多种证据表明 SCZD 具有很强的遗传因素。因此，鉴定与 SCZD 相关的遗传变异可能为理解和治疗该疾病提供关键工具。事实上，最近的全基因组关联研究已经确定了超过 100 个与 SCZD 相关的位点，但这些遗传变异仅占疾病发病率的一小部分。对于这一令人不满意的结果，一个可能的解释是 SCZD 风险等位基因不是通过种系遗传的，而是通过受影响个体神经元内的体细胞突变产生的。也许 SCZD 患者遗传了体细胞嵌合倾向。现在已经清楚，DNA序列的体细胞嵌合现象比以前想象的要普遍得多（即个体内的所有细胞不包含相同的基因组），并且这种现象在大脑中尤其普遍。这些基因组差异可能导致神经元功能的多样性。然而，产生或控制体细胞嵌合的过程失调可能导致与疾病相关的基因组不稳定。因此，我们的假设是神经元或其祖细胞中的体细胞嵌合是 SCZD 发病机制的主要贡献者。目标 1 将使用单细胞基因组测序技术来识别 SCZD 患者或神经型对照患者的神经元和非神经元细胞类型中的体细胞拷贝数变异 (CNV)。这些分析将重点关注额叶皮层和海马体，这两个与 SCZD 发病机制相关的大脑区域。结果将确定体细胞 CNV 在 SCZD 大脑中是否过多，以及 SCZD 风险等位基因是否受到这些 CNV 的不成比例的影响。目标 2 将描述这些相同细胞类型中体细胞逆转录转座子插入的特征，询问与对照组相比，SCZD 患者神经元中逆转录转座事件的频率或位置是否发生改变。目标 1 和 2 将分析总共 8000 个神经元，这使其成为迄今为止对神经元体细胞嵌合体最全面的分析。在目标 3 中，SCZD 患者中最常见的基因组变异（在目标 1 和 2 中确定）将被工程化到 hESC 中进行功能验证测试。研究表明，与对照组相比，来自 SCZD 患者的培养神经元表现出连接水平降低且神经突发育不全。类似的分析将使用源自工程 hESC 的神经元的等基因和嵌合培养物进行。这些研究的结果将确定 SCZD 神经元中体细胞嵌合的水平、模式或类型是否发生改变，并有可能识别受这些变化影响最大的基因和基因网络。确定致病因素将提供新的治疗靶点，并使我们更接近找到治愈这种毁灭性疾病的方法。