TY - JOUR
T1 - Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
AU - Beaudoin, Mélissa
AU - Goyette, Philippe
AU - Boucher, Gabrielle
AU - Lo, Ken Sin
AU - Rivas, Manuel A.
AU - Stevens, Christine
AU - Alikashani, Azadeh
AU - Ladouceur, Martin
AU - Ellinghaus, David
AU - Torkvist, Leif
AU - Goel, Gautam
AU - Lagacé, Caroline
AU - Annese, Vito
AU - Bitton, Alain
AU - Begun, Jakob
AU - Brant, Steve R.
AU - Bresso, Francesca
AU - Cho, Judy H.
AU - Duerr, Richard H.
AU - Halfvarson, Jonas
AU - McGovern, Dermot P. B.
AU - Radford-Smith, Graham L.
AU - Schreiber, Stefan
AU - Schumm, Philip L.
AU - Sharma, Yashoda
AU - Silverberg, Mark S.
AU - Weersma, Rinse K.
AU - Quebec IBD Genetics Consortium (QIGC)
AU - NIDDK IBD Genetics Consortium
AU - International IBD Genetics Consortium
AU - D'Amato, Mauro
AU - Vermeire, Severine
AU - Franke, Andre
AU - Lettre, Guillaume
AU - Xavier, Ramnik J.
AU - Daly, Mark J.
AU - Rioux, John D.
A2 - Aumais, Guy
A2 - Bernard, Edmond Jean
A2 - Cohen, Albert
A2 - Deslandres, Colette
A2 - Lahaie, Raymond
A2 - Paré, Pierre
A2 - Targan, Stephan R.
A2 - Rutgeerts, Paul
A2 - Steinhart, A. Hillary
A2 - Torkvist, Leif
A2 - Ahmad, Tariq
A2 - Anderson, Carl A.
A2 - Baldassano, Robert N.
A2 - Balschun, Tobias
A2 - Barclay, Murray
A2 - Mowat, Craig
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84884683078&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1003723
DO - 10.1371/journal.pgen.1003723
M3 - Article
C2 - 24068945
AN - SCOPUS:84884683078
SN - 1553-7390
VL - 9
JO - PLoS Genetics
JF - PLoS Genetics
IS - 9
M1 - e1003723
ER -