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Systematic in vivo characterization of disease-associated regulatory variants

疾病相关调控变异的系统体内表征

基本信息

批准号：
10472058
负责人：
Michael Isaiah Love
金额：
$ 184.86万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10472058
关键词：
Achievement Affect Algorithms Alleles Bar Codes Biological Assay Blood Circulation Brain Catalogs Cells Clinical Research Code Communities Complex Controlled Study DNA Data Data Collection Disease Environment Exhibits Female Frequencies Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Variation Genetic study Genomic Segment Genomics Goals Health Heart Heterogeneity Human Human Genetics Individual Inflammatory Lead Libraries Link Liver Lung Measurement Mus Muscle Organ Physiological Physiology Positioning Attribute Process Protocols documentation RNA Sequences Rare Diseases Regulator Genes Regulatory Element Reporter Reporting Research Personnel Signal Transduction Testing Tissues Transcriptional Regulation Untranslated RNA Validation Variant Viral Work adeno-associated viral vector base cell type disorder risk experimental study gene environment interaction genetic variant genome wide association study genomic locus genomic variation human genomics in vivo male member network models new therapeutic target prediction algorithm predictive modeling public health relevance risk variant sex trait transcription factor

项目摘要

ABSTRACT Thousands of genetic loci are associated with human traits or disease risk, and these loci each typically contain tens to hundreds of variants, most of which are non-coding and lack direct evidence of effects on genes. Experimental tests of genomic variants are needed to identify functional effects, which can be specific to one sex, tissue, and/or perturbed environmental context. Testing effects of risk variants on gene regulation requires an ability to quantify the potentially modest consequences of thousands of alleles in a carefully controlled study. Our overarching goal is to systematically characterize the impact of human genetic variation on gene regulation via massively parallel reporter assays (MPRA). We will select variants based primarily on genome-wide association studies (GWAS) for common diseases and complex traits relevant to the brain, liver, lung, muscle, and/or heart. We will examine all plausible functional candidates at prioritized GWAS loci to provide data for tests of regulatory variant prediction algorithms, positive control variants, and variants prioritized based on regulatory element annotations. The gene regulatory effect of ~500,000 variant alleles will be interrogated in five organs (brain, liver, lung, muscle and heart) using systemic circulation of adeno-associated viral (AAV) MPRA libraries. We will repeat this experiment in a perturbed inflammatory state to evaluate gene-environment interactions. As a result, we will comprehensively characterize variant effects on regulatory function by analyses of variants in the physiological conditions of multiple tissues, in both sexes, with and without perturbation typical of disease environments. Selected variants will be edited into human pluripotent cells for validation. As members of the Impact of Genomic Variation on Function (IGVF) Consortium, we will generate a regulatory variant catalog for the community, and enable future studies through data collection and predictive models. Successful completion of these aims will provide ~10 million allelic effect data points that encompass tissue-, sex-, and perturbation- specific regulatory effects. We will work with the IGVF consortium to finalize selection of variants, organs, and perturbations to generate a comprehensive catalog. The expertise of the study investigators in GWAS, statistical and computational genetics, human genomics, AAV delivery, and mouse physiology make achievement of these aims feasible and likely highly informative to understand how genomic variation impacts human health and disease.

摘要