R24OD035402

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

Genome-wide association studies (GWAS) have produced a multitude of candidate genes and loci for a wide range of complex diseases 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 different tissues or organs, and the integration of lifelong multidimensional risk in many of the mapped disease traits.

As the field evolves, 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.

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.

Brigham & Womens Hospital

THE OFFICE OF RESEARCH INFRASTRUCTURE PROGRAMS (ORIP) IS A PROGRAM OFFICE IN THE DIVISION OF PROGRAM COORDINATION, PLANNING, AND STRATEGIC INITIATIVES (DPCPSI) DEDICATED TO SUPPORTING RESEARCH INFRASTRUCTURE AND RELATED RESEARCH RESOURCE PROGRAMS. ORIP CONSISTS OF THE DIVISION OF COMPARATIVE MEDICINE (DCM) AND THE DIVISION OF CONSTRUCTION AND INSTRUMENTS (DCI).

93.351 - Research Infrastructure Programs

National Institutes of Health (NIH) [HHS]

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Boston, Massachusetts 021156110 United States

Single Zip Code

Resource-Related Research Projects for Development of Animal Models and Related Materials (R24 Clinical Trials Not-Allowed) (RFA-OD-22-013)

Amendment Since initial award the total obligations have increased 293% from $896,208 to $3,525,582.