Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis
Open accessAbstract
We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease.
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“Although searches have not yet found much evidence for epistasis [e.g., (93, 94, 135)]”
From Genetic Mapping in Human Disease (2008) · cites this paper as [135]
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- Authors
- Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., Shugart, Y. Y., Griffiths, A. M., Targan, S. R., Ippoliti, A. F., Bernard, E.-J., Mei, L., Nicolae, D. L., Regueiro, M., Schumm, L. P., Steinhart, A. H., Rotter, J. I., Duerr, R. H., Cho, J. H., Daly, M. J., & Brant, S. R.
- Affiliations
- Montreal Heart Institute (CA)
- Harvard University (US)
- Cedars-Sinai Medical Center (US)
- Mount Sinai Hospital (CA)
- Broad Institute (US)
- University of Pittsburgh (US)
- Johns Hopkins University (US)
- Hospital for Sick Children (CA)
- Centre Hospitalier de l’Université de Montréal (CA)
- University of Chicago (US)
- Yale University (US)
- Corresponding author
- Rioux, John D
- ORCID
- Venue
- Nature Genetics
- Published
- 2007-04-15
- Volume
- 39
- Issue
- 5
- Pages
- 596-604
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2757939
- OpenAlex
- W2122031852
- Cited by
- 1,769
- References
- 48
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 32 · 2023: 45 · 2022: 35 · 2021: 56 · 2020: 57 · 2019: 73 · 2018: 64 · 2017: 73 · 2016: 78 · 2015: 95 · 2014: 94 · 2013: 130 · 2012: 136
- FWCI
- 109.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Repository@Nottingham (University of Nottingham) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- Cedars-Sinai Medical Center
- National Institute of Allergy and Infectious Diseases (AI 062773, R01AI062773)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK046763, DK62432, DK-46763, DK62431, DK62423, DK62413, DK62422, DK62420, DK62429, U01DK062420, DK 43351, U01DK062429, U24DK062429, U01DK062413, U01DK062422, P30DK063491, U01DK062432, P30DK043351, U01DK062431, P30DK040561, U01DK062423)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- Crohn's disease, genetic susceptibility loci, ATG16L1, autophagy, NOD2, IL23R, PHOX2B, NCF4, Salmonella typhimurium, intestinal epithelial cells, genetic association
- MeSH terms
- Autophagy-Related Proteins, Animals, Autophagy, Carrier Proteins, Chromosomes, Human, Pair 10, Crohn Disease, HeLa Cells, Humans, Immunohistochemistry, North America, Transcription Factors, Homeodomain Proteins, NADPH Oxidases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Gene Expression Profiling, RNA Interference, Mice
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