Biological Sciences Division
Published September 12, 2013 | Version v1
Journal article Open

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

Creators

  • 1. Montreal Heart Institute
  • 2. Broad Institute
  • 3. Christian-Albrechts-University
  • 4. Karolinska Institutet
  • 5. Harvard University
  • 6. Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza Hospital
  • 7. McGill University
  • 8. Johns Hopkins University
  • 9. Karolinska University Hospital
  • 10. Yale University
  • 11. University of Pittsburgh
  • 12. Örebro University
  • 13. Cedars-Sinai Medical Center
  • 14. University of Queensland
  • 15. University of Chicago

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. © 2013 Beaudoin et al.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

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Additional details

Identifiers

DOI
10.1371/journal.pgen.1003723
Other
oai:uchicago.tind.io:10892

Funding

Swedish Society of Medicine
Ihre Foundation
Örebro University Hospital
Research Foundation
Karolinska Institutet
Unknown funder
Swedish National Program for IBD Genetics
Unknown funder
Swedish Organization for IBD
Swedish Research Council
Dutch Research Council
clinical fellowship grant
National Human Genome Research Institute
Deutsche Forschungsgemeinschaft
Cluster of Excellence “Inflammation at Interfaces”
PopGen biobank
National Institute of Diabetes and Digestive and Kidney Diseases
DK062431
National Institute of Diabetes and Digestive and Kidney Diseases
DK062422
National Institute of Diabetes and Digestive and Kidney Diseases
DK062429
National Institute of Diabetes and Digestive and Kidney Diseases
DK062420
National Institute of Diabetes and Digestive and Kidney Diseases
DK062423
National Institute of Diabetes and Digestive and Kidney Diseases
DK062413
National Institute of Diabetes and Digestive and Kidney Diseases
DK062432
National Institute of Diabetes and Digestive and Kidney Diseases
DK064869
Crohn's and Colitis Canada
Canadian Institutes of Health Research
GPG-102170

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Public Health Sciences