Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis

Mélissa Beaudoin, Philippe Goyette, Gabrielle Boucher, Ken Sin Lo, Manuel A. Rivas, Christine Stevens, Azadeh Alikashani, Martin Ladouceur, David Ellinghaus, Leif Törkvist, Gautam Goel, Caroline Lagacé, Vito Annese, Alain Bitton, Jakob Begun, Steve R. Brant, Francesca Bresso, Judy H. Cho, Richard H. Duerr, Jonas HalfvarsonDermot P B McGovern, Graham Radford-Smith, Stefan Schreiber, Philip L. Schumm, Yashoda Sharma, Mark S. Silverberg, Rinse K. Weersma, Mauro D'Amato, Severine Vermeire, Andre Franke, Guillaume Lettre, Ramnik J. Xavier, Mark J. Daly, John D. Rioux, Guy Aumais, Edmond Jean Bernard, Alain Bitton, Albert Cohen, Colette Deslandres, Raymond Lahaie, Pierre Paré, John D. Rioux, Steven R. Brant, Judy H. Cho, Richard H. Duerr, Dermot P B McGovern, John D. Rioux, Mark S. Silverberg, David Ellinghaus, Andre Franke, Stephan R. Targan, Philip Schumm, Paul Rutgeerts, Severine Vermeire, Mark S. Silverberg, A. Hillary Steinhart, Leif Torkvist, Mauro D'Amato, Stefan Schreiber, Tariq Ahmad, Carl A. Anderson, Vito Annese, Robert N. Baldassano, Tobias Balschun, Murray Barclay, Jeffrey C. Barrett, Theodore M. Bayless, Joshua C. Bis, Stephan Brand, Steven R. Brant, Suzanne Bumpstead, Carsten Buning, Judy H. Cho, Albert Cohen, Jean Frederick Colombel, Mario Cottone, Renata D'Inca, Mark J. Daly, Ted Denson, Marla Dubinsky, Richard H. Duerr, Cathryn Edwards, Tim Florin, Denis Franchimont, Richard Gearry, Michel Georges, Jurgen Glas, Andre van Gossum, Anne M. Griffiths, Stephen L. Guthery, Hakon Hakonarson, Talin Haritunians, Jean Pierre Hugot, Dirk J. de Jong, Luke Jostins, Subra Kugathasan, Gerd Kullak-Ublick, Anna Latiano, Debby Laukens, Ian Lawrance, James Lee, Charlie W. Lees, Marc Lemann, Arie Levine, Cecile Libioulle, Edouard Louis, John C. Mansfield, Christopher G. Mathew, Dermot P B McGovern, Mitja Mitrovic, Grant W. Montgomery, Craig Mowat, William Newman, Orazio Palmieri, Julián Panés, Miles Parkes, Anne Phillips, C. Y. Ponsioen, Uros Potocnik, Natalie J. Prescott, Deborah D. Proctor, Graham L. Radford-Smith, Miguel Regueiro, John D. Rioux, Rebecca Roberts, Jerome I. Rotter, Jeremy Sanderson, Miquel Sans, Jack Satsangi, Frank Seibold, Yashoda Sharma, Lisa A. Simms, Kent D. Taylor, Jonas Halfvarson, H. W. Verspaget, Martine de Vos, Thomas Walters, Kai Wang, Rinse K. Weersma, David Whiteman, Cisca Wijmenga

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Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci.

Original languageEnglish
Article numbere1003723
JournalPLoS Genetics
Issue number9
Publication statusPublished - Sept 2013

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)


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