Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease
Open accessAbstract
Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.
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An initial inflammatory bowel disease screen found rare-variant evidence for just one of 63 GWAS-identified genes.
“only 1 of 63 genes in an initial screen for inflammatory bowel disease found evidence for rare variant effects (and these were protective114, but see also115)”
From Rare and common variants: twenty arguments (2012) · cites this paper as [114]
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- Authors
- Momozawa, Y., Mni, M., Nakamura, K., Coppieters, W., Almer, S., Amininejad, L., Cleynen, I., Colombel, J.-F., de Rijk, P., Dewit, O., Finkel, Y., Gassull, M. A., Goossens, D., Laukens, D., Lémann, M., Libioulle, C., O'Morain, C., Reenaers, C., Rutgeerts, P., Tysk, C., Zelenika, D., Lathrop, M., Del-Favero, J., Hugot, J.-P., de Vos, M., Franchimont, D., Vermeire, S., Louis, E., & Georges, M.
- Affiliations
- University of Liège (BE)
- Linköping University (SE)
- Université Libre de Bruxelles (BE)
- KU Leuven (BE)
- Hôpital Albert Calmette (FR)
- Cliniques Universitaires Saint-Luc (BE)
- Hospital Universitari Germans Trias i Pujol (ES)
- University of Antwerp (BE)
- Ghent University Hospital (BE)
- Assistance Publique – Hôpitaux de Paris (FR)
- Tallaght University Hospital (IE)
- Örebro University Hospital (SE)
- Inserm (FR)
- Corresponding author
- Georges, Michel
- ORCID
- Venue
- Nature Genetics
- Published
- 2010-12-12
- Volume
- 43
- Issue
- 1
- Pages
- 43-47
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2147698885
- Cited by
- 189
- References
- 23
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 10 · 2019: 14 · 2018: 7 · 2017: 8 · 2016: 12 · 2015: 15 · 2014: 21 · 2013: 27 · 2012: 26
- FWCI
- 13.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
- ORBi (University of Liège) (submittedVersion, other-oa)
- DIAL (Catholic University of Leuven) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Fonds De La Recherche Scientifique - FNRS
- Belgian Federal Science Policy Office
- Fédération Wallonie-Bruxelles
- Vlaams Instituut voor Biotechnologie
- Université de Liège
- Vlaamse regering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- Crohn's disease, inflammatory bowel disease, IL23R, rare coding variants, positional candidate genes, genetic susceptibility, genetic susceptibility loci
- MeSH terms
- Crohn Disease, Humans, Phenotype, Genetic Variation, Inflammatory Bowel Diseases, Case-Control Studies, Sequence Analysis, DNA, Receptors, Interleukin, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Nod2 Signaling Adaptor Protein, Genome-Wide Association Study
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