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

Beaudoin, M and Goyette, P and Boucher, G and Lo, KS and Rivas, MA and Stevens, C and Alikashani, A and Ladouceur, M and Ellinghaus, D and Törkvist, L and Goel, G and Lagacé, C and Annese, V and Bitton, A and Begun, J and Brant, SR and Bresso, F and Cho, JH and Duerr, RH and Halfvarson, J and McGovern, DPB and Radford-Smith, G and Schreiber, S and Schumm, PL and Sharma, Y and Silverberg, MS and Weersma, RK and D'Amato, M and Vermeire, S and Franke, A and Lettre, G and Xavier, RJ and Daly, MJ and Rioux, JD and Aumais, G and Bernard, EJ and Bitton, A and Cohen, A and Deslandres, C and Lahaie, R and Paré, P and Rioux, JD and Brant, SR and Cho, JH and Duerr, RH and McGovern, DPB and Rioux, JD and Silverberg, MS and Ellinghaus, D and Franke, A and Targan, SR and Schumm, P and Rutgeerts, P and Vermeire, S and Silverberg, MS and Steinhart, AH and Torkvist, L and Schreiber, S and Ahmad, T and Anderson, CA and Annese, V and Baldassano, RN and Balschun, T and Barclay, M and Barrett, JC and Bayless, TM and Bis, JC and Brand, S and Brant, SR and Bumpstead, S and Buning, C and Cho, JH and Cohen, A and Colombel, JF and Cottone, M and D'Inca, R and Daly, MJ and Denson, T and Dubinsky, M and Duerr, RH and Edwards, C and Florin, T and Franchimont, D and Gearry, R and Georges, M and Glas, J (2013) Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis. PLoS Genetics, 9 (9). ISSN 1553-7390

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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.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Beaudoin, M
Goyette, P
Boucher, G
Lo, KS
Rivas, MA
Stevens, C
Alikashani, A
Ladouceur, M
Ellinghaus, D
Törkvist, L
Goel, G
Lagacé, C
Annese, V
Bitton, A
Begun, J
Brant, SR
Bresso, F
Cho, JH
Duerr, RH
Halfvarson, J
McGovern, DPB
Radford-Smith, G
Schreiber, S
Schumm, PL
Sharma, Y
Silverberg, MS
Weersma, RK
D'Amato, M
Vermeire, S
Franke, A
Lettre, G
Xavier, RJ
Daly, MJ
Rioux, JD
Aumais, G
Bernard, EJ
Bitton, A
Cohen, A
Deslandres, C
Lahaie, R
Paré, P
Rioux, JD
Brant, SR
Cho, JH
Duerr, RH
McGovern, DPB
Rioux, JD
Silverberg, MS
Ellinghaus, D
Franke, A
Targan, SR
Schumm, P
Rutgeerts, P
Vermeire, S
Silverberg, MS
Steinhart, AH
Torkvist, L
Schreiber, S
Ahmad, T
Anderson, CA
Annese, V
Baldassano, RN
Balschun, T
Barclay, M
Barrett, JC
Bayless, TM
Bis, JC
Brand, S
Brant, SR
Bumpstead, S
Buning, C
Cho, JH
Cohen, A
Colombel, JF
Cottone, M
D'Inca, R
Daly, MJ
Denson, T
Dubinsky, M
Duerr, RHduerr@pitt.eduDUERR
Edwards, C
Florin, T
Franchimont, D
Gearry, R
Georges, M
Glas, J
Date: 1 September 2013
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 9
Number: 9
DOI or Unique Handle: 10.1371/journal.pgen.1003723
Schools and Programs: Graduate School of Public Health > Human Genetics
School of Medicine > Medicine
Refereed: Yes
ISSN: 1553-7390
Date Deposited: 10 Oct 2013 14:29
Last Modified: 16 Feb 2019 21:55
URI: http://d-scholarship.pitt.edu/id/eprint/19819

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