@article{TEXTUAL,
      recid = {10892},
      author = {Beaudoin, Mélissa and Goyette, Philippe and Boucher,  Gabrielle and Lo, Ken Sin and Rivas, Manuel A. and Stevens,  Christine and Alikashani, Azadeh and Ladouceur, Martin and  Ellinghaus, David and Törkvist, Leif and Goel, Gautam and  Lagacé, Caroline and Annese, Vito and Bitton, Alain and  Begun, Jakob and Brant, Steve R. and Bresso, Francesca and  Cho, Judy H. and Duerr, Richard H. and Halfvarson, Jonas  and McGovern, Dermot P. B. and Radford-Smith, Graham and  Schreiber, Stefan and Schumm, Philip L.},
      title = {Deep Resequencing of GWAS Loci Identifies Rare Variants in  <i>CARD9</i>, <i>IL23R</i> and  <i>RNF186</i> That Are Associated with  Ulcerative Colitis},
      journal = {PLOS Genetics},
      address = {2013-09-12},
      number = {TEXTUAL},
      abstract = {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. © 2013 Beaudoin et al.},
      url = {http://knowledge.uchicago.edu/record/10892},
}