Atlas of Regulatory Variants in Diseases (ARVID)

疾病调控变异图谱 (ARVID)

• 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
• 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' 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

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：疾病调控变异图谱(ARVID) 项目总结 全基因组关联研究已经确定了数以千计的单核苷酸 与罹患特定非癌症多基因疾病风险相关的SNPs， 包括缺血性心脏病，慢性阻塞性肺疾病，阿尔茨海默氏症， 2型糖尿病和缺血性中风。这些与疾病相关的SNPs集中在调节DNA中 活跃于可能通过调节其表达的基因(Egene)而介导疾病风险的细胞类型 水平可能在发病机制中起重要作用。这些疾病相关表达SNPs(ESNPs) 通常改变转录因子(TF)DNA结合基序，表明它们可能影响调控 通过改变基因调节因子的结合来激活DNA。这项U24提案旨在产生一种基因组 参考资料，疾病调控变异图集(ARVID)，包含以下3大类 信息类别：1)差异基因与个体疾病相关的人类eSNP 相关细胞类型的调节功能2)这些eSNPs的靶基因(Egene) 失调和3)基因调节器，这些疾病与eSNPs改变了DNA关联。 首先，我们将在链接到索引SNP的那些eSNP中识别特定的功能改变的eSNP 在上面提到的5种广泛传播的人类疾病中，GWAS使用大量平行的方式确定了 记者分析(MPRA)。由此产生的300个顶级疾病风险和非风险ESNP对的子集将 然后在基因编辑产生的同源细胞中进行深入鉴定，直接鉴定 间接失调的靶基因。这一努力将产生一个)基因组纲要 疾病相关eSNPs对疾病相关细胞DNA调控功能的定量影响 B)300个顶级疾病eSNPs的致病基因类型。 其次，我们将确定其DNA关联在300处发生改变的特定基因调节器 疾病风险eSNPs，与匹配的非风险等位基因相比。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 使用等压标记的光谱将得到定量染色质的补充 免疫沉淀(CHIP)分析使用的是同基因的、与疾病相关的细胞，这些细胞只在 感兴趣的单一ESNP核苷酸。这一努力将产生差异调节蛋白图谱 结合300个参照病ESNP对。 这个NHGRI U24将产生一个基因组资源，定义DNA变体、靶基因和 基因调控因子参与了人类5种常见非癌性多基因疾病的遗传风险。