A community resource for germline and somatic genetic disease modeling in zebrafish

Summary Genome wide associations studies (GWAS) have produced a multitude of candidate genes and loci for a wide range of complex disease and phenotypic traits, but often have not resulted in sufficient mechanistic insight to lead to actionable changes in prevention, diagnosis, or treatment of disease. This is a consequence of key

attributes of the underlying genetic effects which can prove difficult to model, specifically: combinatorial interactions between multiple loci, a preponderance of regulatory effects which may act at different times and in in different tissues or organs, and the integration of lifelong multidimensional risk in many of the mapped disease

traits. As the field evolves, so other contributions have begun to be recognized at specific loci including; modification of the effects of existing Mendelian genes, more complex gene-gene or gene-environment interactions and a role for somatic variation contributing to diverse chronic diseases. We have successfully overcome these challenges in our existing Zebrafish GWAS Community Resource by

creating a pipeline which exploits the strengths of rapid scalability, functional relevance and genomic conservation of the zebrafish model system to generate useful functional annotation of over 100 genes and regulatory loci over the last 7-years. We have defined the disease gene(s) for multiple GWAS loci in parallel and

moved the field forward to early mechanistic studies. We now propose to extend this Community Resource, continuing our existing activities while adding key capabilities in a) modeling gene-gene and gene environment interactions to further explore the complex genetics of numerous common diseases and the b) definitive

modeling of somatic variation including efficient transplantation studies to fully understand the role of somatic variation in disease. These new capabilities also directly address ongoing requests from the human genetics community for which the resource was originally developed. As a consortium, we will continue to push forward the capabilities of the zebrafish as a model organism in this

field and as costs drop, the number of diseases/loci that we will be able to functionally annotate will only grow through the duration of the proposal. Importantly, we will be able to deliver a comprehensive package of annotated candidate genes and interactions back to our collaborators in the human genetics community to

enhance the impact and insight derived from their studies. For this renewal application, we propose 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.

Aim 2 - Quantitatively characterize gene-gene and gene-environment interactions where these have been implicated in human genetics Aim 3 - Modeling the role of somatic variation at GWAS loci in chronic disease