2/3 Schizophrenia Genetics and Brain Somatic Mosaicism

2/3 精神分裂症遗传学和脑体细胞​​镶嵌

• 批准号: 8878527
• 负责人: JOHN V. MORAN
• 金额: $ 73.65万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878527
• 关键词: Accounting; Adult; Affect; Architecture; Autopsy; Behavioral; Brain; Brain region; Cell Nucleus; Cells; Clinical; Collaborations; Complement; Copy Number Polymorphism; Cultured Cells; DNA; DNA Sequence; Data; Defect; Detection; Diagnosis; Disease; Electroporation; Engineering; Etiology; Event; Exhibits; Family; Fibroblasts; Frequencies; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Genome; Genomic Instability; Genomics; Goals; Hallucinations; Hippocampus (Brain); Human; Human Genetics; Impaired cognition; Impairment; Incidence; Individual; Inherited; Lead; Libraries; Location; Mobile Genetic Elements; Molecular; Mosaicism; Mutation; Nature; Neurites; Neurobiology; Neuroglia; Neurology; Neurons; Paranoia; Partner in relationship; Pathogenesis; Patients; Pattern; Population; Process; Psychiatry; Public Health; RNA; Reading; Relative (related person); Research; Research Personnel; Retrotransposition; Retrotransposon; Sampling; Schizophrenia; Somatic Mutation; Sorting - Cell Movement; Stem cells; Symptoms; Techniques; Testing; Validation; Variant; Work; base; brain tissue; cell type; disorder risk; exome; exome sequencing; frontal lobe; genetic variant; genome editing; genome sequencing; genome wide association study; genomic variation; human embryonic stem cell; improved; in utero; member; mouse model; neural circuit; neurodevelopment; neuron development; neuropsychiatry; new therapeutic target; progenitor; programs; public health relevance; research study; risk variant; tool; transcriptome sequencing

 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（由适用提供）：精神分裂症（SCZD）是一种令人衰弱的，通常无法治愈的神经精神疾病，影响了1％的人口。疾病症状包括幻觉，偏执狂和认知受损，被认为是由于神经元连通性和可塑性的损害引起的，但这些缺陷的病因尚不清楚。多种证据表明SCZD具有强大的遗传成分。这是识别与SCZD相关的遗传变异可能会提供理解和治疗疾病的关键工具。实际上，最近的基因组广泛的关联研究已经确定了与SCZD相关的100个基因座，但是这些遗传变异仅占疾病入口的一小部分。这一不满意结果的一种潜在解释是，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的神经元内的体细胞突变而产生的。也许是SCZD患者遗传的躯体镶嵌的希望。现在很明显，DNA序列的体细胞镶嵌物比以前想象的要普遍得多（即，个体中的所有细胞都不包含相同的基因组），并且这种现象在大脑中尤为普遍。这些基因组差异可能有助于神经元功能的多样性。但是，产生或控制体细胞镶嵌的过程的失调可能导致与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镶嵌是造成SCZD发病机理的主要因素。 AIM 1将使用单细胞基因组测序技术来鉴定SCZD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体（CNV）。这些分析将集中于额叶皮层和海马，这是与SCZD发病机理相关的两个大脑区域。结果将确定SCZD大脑中的体细胞CNV是否代表过多，以及SCZD风险等位基因是否受这些CNV的影响不成比例。 AIM 2将表征这些相同细胞类型中的体细胞返回跨座子插入，询问与对照组相比，SCZD患者的神经元中逆转录事件的频率或位置是否改变了。 AIMS 1和2中将总共分析8000个神经元，这使得这是对迄今为止神经元体细胞镶嵌的最全面分析。在AIM 3中，SCZD患者（在AIMS 1和2中确定）中最多的基因组变异将被设计到hESC中进行功能验证测试。已经表明，源自SCZD患者的培养神经元暴露于降低的连通性水平，并且与对照组相比，神经运动不发达。使用来自工程hESC的神经元的同基因和镶嵌培养物进行类似的分析。这些研究的结果将确定SCZD神经元中体细胞镶嵌的水平，模式或类型是否会改变，并有可能识别受这些变化影响最大的基因和基因网络。识别催化疾病因素将为我们提供新的治疗靶标，并使我们更加接近找到这种毁灭性疾病的方法。