UM1HG012003

Systematic In Vivo Characterization of Disease-Associated Regulatory Variants - 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.

University Of North Carolina At Chapel Hill

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Chapel Hill, North Carolina 27599 United States

Single Zip Code

Systematic Characterization of Genomic Variation on Genomic Function and Phenotype (UM1 Clinical Trial Not Allowed) (RFA-HG-20-043)

Amendment Since initial award the total obligations have increased 792% from $924,412 to $8,244,979.