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Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease
Open accessAbstract
Previous genome-wide association (GWA) studies typically focus on single-locus analysis, which may not have the power to detect the majority of genuinely associated loci. Here, we applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium (WTCCC) and uncovered significant association between Crohn Disease (CD) and the IL12/IL23 pathway, harboring 20 genes (p = 8 x 10(-5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2) or homologs of genes (STAT3 and CCR6) that were recently identified as genuine susceptibility genes only through meta-analysis of several GWA studies. In addition, the pathway contains other susceptibility genes for CD, including IL18R1, JUN, IL12RB1, and TYK2, which do not reach genome-wide significance by single-marker association tests. The observed pathway-specific association signal was subsequently replicated in three additional GWA studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Our study suggests that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to unleashing the true power of GWA studies.
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Metadata
- Authors
- Wang, K., Zhang, H., Kugathasan, S., Annese, V., Bradfield, J. P., Russell, R. K., Sleiman, P. M. A., Imielinski, M., Glessner, J., Hou, C., Wilson, D. C., Walters, T., Kim, C., Frackelton, E. C., Lionetti, P., Barabino, A., Van Limbergen, J., Guthery, S., Denson, L., Piccoli, D., Li, M., Dubinsky, M., Silverberg, M., Griffiths, A., Grant, S. F. A., Satsangi, J., Baldassano, R., & Hakonarson, H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Emory University (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Edinburgh (GB)
- University of Toronto (CA)
- Meyer Children's Hospital (IT)
- Istituto Giannina Gaslini (IT)
- University of Utah (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Pennsylvania (US)
- Cedars-Sinai Medical Center (US)
- Mount Sinai Hospital (CA)
- Western General Hospital (GB)
- Corresponding author
- Hakonarson, Hakon
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 84
- Issue
- 3
- Pages
- 399-405
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2668006
- OpenAlex
- W2006543991
- Cited by
- 291
- References
- 40
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 12 · 2023: 12 · 2022: 9 · 2021: 12 · 2020: 11 · 2019: 3 · 2018: 7 · 2017: 13 · 2016: 20 · 2015: 21 · 2014: 20 · 2013: 34 · 2012: 33
- FWCI
- 20.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Florence Research (University of Florence) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health (UL1TR000077)
- National Institute of Diabetes and Digestive and Kidney Diseases (K23DK069513, DK 069513, P30DK063491)
- National Center for Research Resources (C06RR011234, M01-RR 00064, M01RR002172, M01RR000064)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- Crohn's disease, pathway analysis, genetic susceptibility, IL12B, JAK2, STAT3, CCR6, IL18R1, c-Jun, IL12RB1, TYK2, gene networks
- MeSH terms
- Crohn Disease, Humans, Signal Transduction, Interleukin-12, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Databases, Genetic, Interleukin-23, Genome-Wide Association Study
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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