Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis

Beaudoin, Melissa, Goyette, Philippe, Boucher, Gabrielle, Lo, Ken Sin, Rivas, Manuel A., Stevens, Christine, Alikashani, Azadeh, Ladouceur, Martin, Ellinghaus, David, Torkvist, Leif, Goel, Gautam, Lagace, Caroline, Annese, Vito, Bitton, Alain, Begun, Jakob, Brant, Steve R., Bresso, Francesca, Cho, Judy H., Duerr, Richard H., Halfvarson, Jonas, McGovern, Dermot P. B., Radford-Smith, Graham, Schreiber, Stefan, Schumm, Philip L., Sharma, Yashoda, Silverberg, Mark S., Weersma, Rinse K., D'Amato, Mauro, Vermeire, Severine, Franke, Andre, Lettre, Guillaume, Xavier, Ramnik J., Daly, Mark J. and Rioux, John D. (2013) Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genetics, 9 9: e1003723.1-e1003723.11. doi:10.1371/journal.pgen.1003723


Author Beaudoin, Melissa
Goyette, Philippe
Boucher, Gabrielle
Lo, Ken Sin
Rivas, Manuel A.
Stevens, Christine
Alikashani, Azadeh
Ladouceur, Martin
Ellinghaus, David
Torkvist, Leif
Goel, Gautam
Lagace, Caroline
Annese, Vito
Bitton, Alain
Begun, Jakob
Brant, Steve R.
Bresso, Francesca
Cho, Judy H.
Duerr, Richard H.
Halfvarson, Jonas
McGovern, Dermot P. B.
Radford-Smith, Graham
Schreiber, Stefan
Schumm, Philip L.
Sharma, Yashoda
Silverberg, Mark S.
Weersma, Rinse K.
D'Amato, Mauro
Vermeire, Severine
Franke, Andre
Lettre, Guillaume
Xavier, Ramnik J.
Daly, Mark J.
Rioux, John D.
Title Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis
Formatted title
Deep resequencing of GWAS loci identifies rare variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis
Journal name PLoS Genetics   Check publisher's open access policy
ISSN 1553-7390
1553-7404
Publication date 2013-09-01
Sub-type Article (original research)
DOI 10.1371/journal.pgen.1003723
Open Access Status DOI
Volume 9
Issue 9
Start page e1003723.1
End page e1003723.11
Total pages 11
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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