Crohn’s & Colitis Congress™

Sessions Speakers Exhibitors Floor Plan Buzz

P164 - USING EXOME SEQUENCING TO EXPAND THE GENETIC ARCHITECTURE OF INFLAMMATORY BOWEL DISEASE (Room Poster Hall)

Background: IBD studies over the past decade have confirmed association to 250 gene loci. A handful of associations have led to specific validated functional variants highlighting intracellular response to microbes and regulation of adaptive immunity in IBD pathogenesis. For the vast majority, however, the specific implicated gene and causal functional variants remain unknown. Methods: In partnership with IBD researchers around the world, we launched an exome sequencing initiative to define the full allelic spectrum of protein-altering variation in genes associated to CD and/or UC, assess their role in clinical course and response to therapy, and to determine whether truncating variants confer risk or protection in each IBD gene in order to highlight opportune therapeutic targets. Results: We have already completed exomes of 13,000 IBD cases providing a high-resolution view of coding variation at each GWAS hit and demonstrated a convincing excess of rare exome signal collectively. The cases are drawn from individual substudies that focus on isolated populations (Ashkenazi, Finnish, French-Canadian), admixed populations and clinical extremes, each providing unique opportunities for discovery. Early findings include novel protective truncating variants, the complete allelic series (including unique founder population alleles), non-additive inheritance models at known genes such as NOD2, overlooked low-frequency coding variants that explain GWAS hits (PRDM1, NRIP1). The integration of low frequency and rare functional variants with GWAS is moving us much closer towards completion of the genetic architecture of IBD. Conclusion: Early analyses of the data have revealed novel non-coding associations in known IBD genes as well as coding variants that implicate genes at loci in which the ‘causative’ gene was unknown. Furthermore, initial results have suggested variation in enrichment of different processes across different ethnicities.