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

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 tremendou...

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Main Authors:	Beaudoin, Mélissa, Goyette, Philippe, Boucher, Gabrielle, Lo, Ken Sin, Rivas, Manuel A., Stevens, Christine, Alikashani, Azadeh, Ladouceur, Martin, Ellinghaus, David, Törkvist, Leif, Goel, Gautam, Lagacé, 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.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772057/

id	pubmed-3772057
recordtype	oai_dc
spelling	pubmed-37720572013-09-25 Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis Beaudoin, Mélissa Goyette, Philippe Boucher, Gabrielle Lo, Ken Sin Rivas, Manuel A. Stevens, Christine Alikashani, Azadeh Ladouceur, Martin Ellinghaus, David Törkvist, Leif Goel, Gautam Lagacé, 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. Research Article 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. Public Library of Science 2013-09-12 /pmc/articles/PMC3772057/ /pubmed/24068945 http://dx.doi.org/10.1371/journal.pgen.1003723 Text en © 2013 Beaudoin et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Beaudoin, Mélissa Goyette, Philippe Boucher, Gabrielle Lo, Ken Sin Rivas, Manuel A. Stevens, Christine Alikashani, Azadeh Ladouceur, Martin Ellinghaus, David Törkvist, Leif Goel, Gautam Lagacé, 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.
spellingShingle	Beaudoin, Mélissa Goyette, Philippe Boucher, Gabrielle Lo, Ken Sin Rivas, Manuel A. Stevens, Christine Alikashani, Azadeh Ladouceur, Martin Ellinghaus, David Törkvist, Leif Goel, Gautam Lagacé, 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. Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
author_facet	Beaudoin, Mélissa Goyette, Philippe Boucher, Gabrielle Lo, Ken Sin Rivas, Manuel A. Stevens, Christine Alikashani, Azadeh Ladouceur, Martin Ellinghaus, David Törkvist, Leif Goel, Gautam Lagacé, 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.
author_sort	Beaudoin, Mélissa
title	Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
title_short	Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
title_full	Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
title_fullStr	Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
title_full_unstemmed	Deep Resequencing of GWAS Loci Identifies Rare Variants in CARD9, IL23R and RNF186 That Are Associated with Ulcerative Colitis
title_sort	deep resequencing of gwas loci identifies rare variants in card9, il23r and rnf186 that are associated with ulcerative colitis
description	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.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772057/
_version_	1612011368347598848

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

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