Gene discoveries in subjects with Crohn's disease of African descent

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ABSTRACT Crohn’s disease (CD) is heritable. Most genetic discovery to date has been performed in Caucasians of European descent. African Americans (AAs) endure a similar disease burden as Caucasians, yet less than 1% of research, publications, or clinical trials have focused on AA with CD. It remains to be seen whether these genetic markers will have prognostic utility in admixed individuals, such as AAs. Furthermore, AAs are at higher risk for disease complications and often have worse disease outcomes, suggesting that the underlying biology of CD in AAs may be different than Caucasians. The genome of AAs is admixed (~80% West African and 20% Caucasian), with greater diversity and shorter linkage disequilibrium (LD) blocks. Higher levels of diversity can make genetic / post-GWAS studies more challenging, but identifying causal variants in AA may prove easier because of shorter physical LD region. We have successfully completed a well-powered GWAS for gene discoveries in AA. While common susceptibility variants discovered in Caucasians are also generally found in AAs with IBD, new AA-specific variants/loci in IBD, UC and human leukocyte antigen (HLA) region along with several new regions of significant admixture linkage disequilibrium and multiple new signaling pathways. Following these exciting results and discoveries, we propose a post GWAS studies to comprehensively identify rare, causal and population specific variants in African Americans with CD. Aim 1: We will double our AA cohort size by additional recruitment and fine map AA- specific and common (to both Caucasians and AA) GWAS loci to test the hypothesis that causal variants can be identified more easily due to shorter LD among AAs. Aim 2: Test the hypothesis that expression quantitative trait loci (eQTL) and gene network analysis will identify new AA-specific regulatory elements and causal loci / rare variants. Aim 3: Perform whole genome sequencing (WGS) in AA cases for rare variant discovery. We propose that post GWAS studies such as fine mapping, eQTL, and WGS in AA should be conducted in parallel to Caucasians, to accelerate gene and pathway discovery in IBD. Proposed efforts will be jointly undertaken with NIDDKGC utilizing their available resources.