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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

基本信息

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
项目类别：
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

项目摘要

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.