Atlas of Regulatory Variants in Diseases (ARVID)

疾病调控变异图谱 (ARVID)

基本信息

批准号：
10242784
负责人：
PAUL KHAVARI
金额：
$ 65.73万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10242784
关键词：
ATAC-seq Affect Alleles Alzheimer&apos s Disease Atlases Binding Biochemical Biological Assay Categories Cell Lineage Cells Chromatin Chronic Obstructive Airway Disease Clinical Communities Complement DNA DNA Binding DNA Sequence DNA-Protein Interaction Data Detection Disease Enhancers Gene Expression Genes Genomics Genotype-Tissue Expression Project Hereditary Disease Human In Situ Individual Inherited Ischemic Stroke Link Maps Mass Spectrum Analysis Mediating Methods Myocardial Ischemia National Human Genome Research Institute Nature Non-Insulin-Dependent Diabetes Mellitus Nucleotides Pathogenesis Pathogenicity Proteins Proteome Proteomics Quantitative Trait Loci RNA Regulator Genes Reporter Resources Risk Single Nucleotide Polymorphism Speed Tissues Untranslated RNA Variant cell type chromatin immunoprecipitation cost data resource disorder risk epigenomics genetic variant genome resource genome wide association study human disease indexing insight interest mortality prevent promoter transcription factor years of life lost

项目摘要

NHGRI U24: ATLAS OF REGULATORY VARIANTS IN DISEASE (ARVID) PROJECT SUMMARY Genome-wide association studies (GWAS) have identified thousands of single nucleotide polymorphisms (SNPs) linked to risk of developing specific non-cancerous polygenic diseases, including ischemic heart disease, chronic obstructive pulmonary disease, Alzheimer’s dementia, type 2 diabetes, and ischemic stroke. These disease-linked SNPs concentrate in regulatory DNA active in cell types that may mediate disease risk by modulating genes (eGenes) whose expression levels may be important in pathogenesis. These disease-linked expression SNPs (eSNPs) commonly alter transcription factor (TF) DNA binding motifs, indicating they may affect regulatory DNA activity by changing gene regulator binding. This U24 proposal aims to generate a genomic resource, the Atlas of Regulatory Variants in Disease (ARVID), containing the following 3 broad categories of information: 1) the individual disease-linked human eSNPs with differential gene regulatory function in relevant cell types 2) the target genes (eGenes) that these eSNPs dysregulate and 3) the gene regulators whose DNA association such disease eSNPs alter. First, we will identify the specific functionally altered eSNPs among those linked to index SNPs identified by GWAS in the 5 widespread human diseases noted above using massively parallel reporter assays (MPRA). A resulting subset of 300 top disease risk and non-risk eSNP pairs will then be deeply characterized in isogenic cells generated by gene editing to identify directly and indirectly dysregulated target genes. This effort will produce a Genomic Compendium of a) the disease-linked eSNPs that quantitatively impact regulatory DNA function in disease-relevant cell types and of b) the eGenes for the 300 top disease eSNPs. Second, we will identify the specific gene regulators whose DNA association is altered at the 300 disease risk eSNPs above, compared to matched non-risk alleles. To do this, we will use a live-cell proteomics approach termed DNA Protein Interaction Detection (DAPID). Quantitative mass spectrometry using isobaric tagging will be complemented by quantitative chromatin immunoprecipitation (ChIP) assays using isogenic, disease-relevant cells that differ only at the single eSNP nucleotide of interest. This effort will produce a Proteomic Atlas of differential regulator binding at 300 reference-disease eSNP pairs. This NHGRI U24 will generate a genomic resource defining the DNA variants, target genes, and gene regulators involved in inherited risk for 5 common non-cancerous polygenic human diseases.

NHGRI U24：疾病调节变体的地图集（ARVID）项目摘要全基因组关联研究（GWAS）已经鉴定出数千个单核苷酸多态性（SNP）与患有特定非癌性多基因疾病的风险有关，包括缺血性心脏病，慢性阻塞性肺疾病，阿尔茨海默氏症的痴呆症， 2型糖尿病和缺血性中风。这些疾病连接的SNP集中在调节性DNA中活跃于可能通过调节基因（EGENES）表达的细胞类型中的细胞类型水平在发病机理中可能很重要。这些疾病连接的表达SNP（ESNP）通常改变转录因子（TF）DNA结合基序，表明它们可能影响调节 DNA活性通过改变基因调节剂结合。该U24提案旨在产生基因组资源，疾病中调节变异的地图集（ARVID），其中包含以下3个宽度信息类别：1）具有差异基因的单个疾病连接的人ESNP 相关细胞类型的调节功能2）这些ESNP的靶基因（EGENES）失调和3）基因调节剂的DNA关联这种疾病ESNP改变。首先，我们将确定与索引SNP链接的特定功能更改的ESNP GWAS在上述5个宽度的人类疾病中使用大量平行指出记者分析（MPRA）。由此产生的300个最高疾病风险和非风险ESNP对的子集将然后在通过基因编辑产生的同源细胞中深入特征，以直接识别间接失调的靶基因。这项工作将产生a）的基因组纲要疾病连接的ESNP，对疾病中疾病的细胞中定量影响调节性DNA功能 b）300个顶级疾病ESNP的Egenes。其次，我们将确定在300处改变DNA关联的特定基因调节剂与匹配的非风险等位基因相比，疾病风险上述ESNP。为此，我们将使用一个活细胞蛋白质组学方法称为DNA蛋白相互作用检测（DAPID）。定量质量使用同余标记的光谱法将通过定量染色质完成免疫沉淀（CHIP）测定使用同基因的，与疾病相关的细胞，仅在感兴趣的单个ESNP核苷酸。这项工作将产生差分调节剂的蛋白质组学图集在300个参考疾病的ESNP对下结合。该NHGRI U24将产生定义DNA变体，靶基因和的基因组资源涉及5种常见的非癌性人类疾病的遗传风险的基因调节剂。