PROJECT SUMMARY/ABSTRACT Inflammatory bowel diseases (IBD) are a group of chronic, debilitating disorders of the gastrointestinal tract with peak onset in adolescence and early adulthood. More than 3 million people are affected in U.S., with an estimated direct healthcare cost of $6.3 billion per year. IBD are highly heritable, thus, studying the genetic basis of IBD is a natural path towards elucidating the IBD pathogenesis, which is poorly understood at present. Genome-wide association studies have identified over 240 loci associated with IBD. These associations typically implicate large genomic regions with hundreds of variants due to the linkage disequilibrium (LD). The latest IBD fine-mapping study resolved the LD and mapped 45 IBD associations to single-variant resolution, providing insights into how genetic variants contribute to IBD pathogenesis in a tissue specific manner. Despite of this initial success, most IBD associations and putative causal variants to date were derived from European ancestries with uncertainty in their transferability to non-European ancestries; and the functional impact for most IBD causal variants, especially the noncoding variants, is unclear. This proposed study bridges these gaps through an integrative strategy combining fine-mapping on a large-scale multi-ancestry IBD cohort and well-designed functional experiments to investigate the genetic basis of IBD. This cohort includes subjects of four ancestral populations including African, admixed American, East Asian and European, with an unprecedented sample size of over 192,600 IBD cases, 3x, 12x, 5x and 3x of the current IBD sample size for each ancestry respectively. A large amount of exome sequencing (WES) data will be included, allowing us to investigate the contribution from rare coding variants which have been shown to be important to IBD and help to link noncoding variants to their gene targets. Extensive quality control and harmonization will be performed to generate a high quality, high coverage individual-level dataset with minimal heterogeneity across ancestries, technologies, and batches. A novel fine-mapping method will be developed to leverage the genomic diversity across ancestries and the WES data with the goal to enhance the fine-mapping resolution especially in the coding genome. Over 200 new IBD causal variants are expected from this study, including many that have large effects and directly disrupt protein functions. These variants will be characterized for their molecular and cellular mechanism in IBD in human T cells using pooled CRISPR activation and CRISPR interference experiments, and knockins of coding variants for their effects on gene regulation in resting and stimulated cells. The new IBD causal variants and biology from this study will provide new insights into IBD pathogenesis, make important positive impact and serve as the fundamental resource and basis toward novel IBD therapeutics.