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Atlas of Regulatory Variants in Diseases (ARVID)

疾病调控变异图谱 (ARVID)

基本信息

批准号：
10022056
负责人：
PAUL KHAVARI
金额：
$ 65.07万
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/10022056
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：疾病调节变异图谱（arvid）