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