Our proposal ?Community Zebrafish Resource for Modeling GWAS Biology? applies novel approaches, algorithms and methods developed within our consortium for functional analysis of human GWAS hits using the zebrafish model system. Our consortium has accumulated broad experience in zebrafish genetics, genome editing, bioinformatics, functional assay development, and human disease modeling as well as innovative mechanistic studies to elucidate individual gene function. During the previous cycle of the award, we established efficient high-content platforms for the functional analysis of coding sequence variation in zebrafish to complement GWAS projects across a variety of complex human traits, and provided pathway entry points and genetic models for understanding disease. In this renewal application, we extend our functional exploration of single and/or multiple GWAS loci and their roles in biological networks underlying human medical traits to include prevalent non-coding variation and drug responses through the following Specific Aims:
Aim 1 -Functionally analyze loci from multiple GWAS studies on blood, liver, heart and vessel traits, optimizing assay development and gene editing using CRISPR-Cas9 technology in zebrafish. a) Using validated assays we will examine the function of multiple coding genes in GWAS loci and generate genetic models in the zebrafish using CRISPR-Cas9 technology. b) Accelerate in vivo gene function evaluation by optimization of genome editing in zebrafish using the CRISPR-Cas9 technology.
Aim 2 -Survey landscapes of genomic regulatory regions in different cell lineages in zebrafish and use the information to support better mapping and functional evaluation of regulatory variants from GWAS loci. a) Using ATAC-seq, ChIP-seq, Methyl-seq, and companion RNA-seq analyses we will establish a comprehensive database of conserved (orthologous) regulatory regions in different cell lineages and organs of both zebrafish and human. We will define regulatory regions in different cell types at different developmental stages which are important for cell lineage differentiation, maintenance and function in zebrafish. b) We will map regulatory effects from GWAS loci to conserved zebrafish regulatory regions and test individual and/or multiple regulatory effects for their roles in specific GWAS traits using genome editing technology and validated functional assays in zebrafish. c) Categorize conserved GWAS loci based on function and catalog genome editing reagents for disease modeling and mechanistic studies and drug discovery.

Public Health Relevance

Human genomic studies have identified large numbers of loci associated with multiple common complex human diseases and have far outstripped traditional experimental approaches for underlying disease mechanisms. We demonstrated the utility of the zebrafish in identifying the functionally relevant genes at GWAS loci and in understanding the molecular mechanisms by which these genes affect the human traits. The current proposal will continue these highly successful efforts while extending our established community resource to support more investigators and broader classes of genomic variation. The core functions of the resource are to efficiently confirm the function of genes and regulatory elements underlying human disease biology and to produce relevant animal models that support in-depth studies of disease mechanism or potentially drug discovery.

National Institute of Health (NIH)
Office of The Director, National Institutes of Health (OD)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZRG1)
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Contreras, Miguel A
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Brigham and Women's Hospital
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