Atlas of Regulatory Variants in Diseases (ARVID)

疾病调控变异图谱 (ARVID)

• 批准号: 10626814
• 负责人: PAUL KHAVARI
• 金额: $ 66.69万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10626814
• 关键词: ATAC-seq; Affect; Alleles; Alzheimer' s Disease; Atlases; Binding; Biochemical; Biological Assay; Categories; Cell Lineage; Cells; Chromatin; Chronic Obstructive Pulmonary 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; 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; genome-wide analysis; human disease; improved; indexing; insight; interest; mortality; prevent; promoter; transcription factor; years of life lost

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（ARVID）调节变量图谱 项目摘要 全基因组关联研究（GWAS）已经确定了数千个单核苷酸 多态性（SNP）与发展特定非癌性多基因疾病的风险有关， 包括缺血性心脏病，慢性阻塞性肺病，阿尔茨海默氏痴呆症， 2型糖尿病和缺血性中风。这些与疾病相关的SNP集中在调控DNA中， 在细胞类型中有活性，可能通过调节基因（eGenes）介导疾病风险， 水平可能在发病机制中很重要。这些疾病相关的表达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 通过改变基因调节剂结合的DNA活性。U24计划的目的是产生一个基因组 资源，疾病的监管变体（ARVID）地图集，包含以下3大 信息类别：1）具有差异基因的个体疾病相关人类eSNPs 2）这些eSNP在相关细胞类型中的靶基因（eGenes） 失调和3）其DNA相关性的基因调节剂，这些疾病eSNP改变。 首先，我们将在那些与索引SNP相关的eSNP中识别出特定的功能改变的eSNP GWAS在上述5种广泛存在的人类疾病中使用大规模平行 报告基因测定（MPRA）。得到的300个最高疾病风险和非风险eSNP对的子集将 然后在基因编辑产生的同基因细胞中进行深入表征，直接鉴定， 间接失调的靶基因。这项工作将产生一个基因组纲要a） 定量影响疾病相关细胞中调节DNA功能疾病相关eSNP 类型和B）300种顶级疾病eSNP的eGenes。 第二，我们将确定特定的基因调控，其DNA关联在300 与匹配的非风险等位基因相比，上述疾病风险eSNP。为此，我们将使用活细胞 蛋白质组学方法称为DNA蛋白质相互作用检测（DAPID）。定量质量 使用同量异位素标记的光谱分析将由定量染色质补充 免疫沉淀（ChIP）测定使用同基因的、疾病相关的细胞，其仅在 目的单个eSNP核苷酸。这项工作将产生一个差异调节蛋白质组图谱 在300个参考-疾病eSNP对处结合。 该NHGRI U24将生成定义DNA变体、靶基因和 与5种常见的非癌性多基因人类疾病的遗传风险有关的基因调节因子。