Functional Screen of Genes within IBD GWAS Loci

September 2020 Council

Lead Division/Office

DDN

Point(s) of Contact

Robert W. Karp, Ph.D.

Executive Summary

Although genome-wide association studies (GWAS) have identified >250 loci associated with Inflammatory Bowel Disease (IBD), most of these loci include 5-20 genes of diverse functions. In order to promote the translation of the genetic associations into a deeper understanding of the pathophysiology of IBD, functional screens are required to identify the underlying causal genes. The human innate immune system and intestinal epithelium, both of which are intimately involved in the pathophysiology of IBD, are strongly homologous to their counterparts in zebrafish, and both species share pathways regulating the development of these systems. Powerful methods are available for genetic manipulation and high-throughput functional screening in zebrafish, and functional screening of zebrafish orthologues of human genes from GWAS loci has been successfully piloted. In this initiative, investigators will develop IBD-related assays of innate immune and intestinal epithelial barrier function in zebrafish and use them to screen zebrafish orthologues of human genes located in IBD-associated loci. They will validate zebrafish genes which alter function in these assays using Phenome-Wide Association Studies (PheWAS) in IBD patient. and healthy controls, and human-based in vitro and ex vivo assays.