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1%的人群。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和可塑性的损伤引起的，但这些缺陷的病因尚不清楚。多种证据表明SCZD有很强的遗传成分。因此，识别与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>100个与SCZD相关的基因座，但这些遗传变异仅占疾病发病率的一小部分。对这一不令人满意的结果的一个潜在解释是，SCZD风险等位基因不是通过生殖系遗传的，而是通过受影响个体的神经元内的体细胞突变产生的。也许这是体细胞嵌合体的倾向，是遗传在SCZD患者。现在清楚的是，DNA序列的体细胞镶嵌比以前认为的要普遍得多（即，一个人体内的所有细胞不包含相同的基因组），这种现象在大脑中特别普遍。这些基因组差异可能有助于神经元功能的多样性。然而，产生或控制体细胞嵌合体的过程的失调可能导致疾病相关的基因组不稳定性。因此，我们的假设是，神经元或其祖细胞中的体细胞嵌合体是SCZD发病机制的主要贡献者。目的1将使用单细胞基因组测序技术来鉴定SCZD患者或神经型对照的神经元和非神经元细胞类型中的体细胞拷贝数变异（CNVs）。这些分析将集中在额叶皮层和海马，与SCZD发病机制相关的两个大脑区域。结果将确定体细胞CNVs是否在SCZD大脑中过度表达，以及SCZD风险等位基因是否不成比例地受到这些CNVs的影响。目的2将表征这些相同细胞类型中的体细胞反转录转座子插入，询问与对照组相比，SCZD患者神经元中反转录转座子事件的频率或位置是否改变。在目标1和2中，将分析总共8000个神经元，使其成为迄今为止对神经元体细胞嵌合性的最全面分析。在目标3中，SCZD患者中最多的基因组变体（在目标1和2中鉴定）将被工程改造成hESC用于功能验证测试。已经表明，与对照组相比，来自SCZD患者的培养神经元表现出降低的连接水平，并且具有不发达的神经突。将使用源自工程化hESC的神经元的同基因和嵌合培养物进行类似的分析。这些研究的结果将确定SCZD神经元中体细胞嵌合体的水平、模式或类型是否改变，并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，并使我们更接近于找到治愈这种毁灭性疾病的方法。