Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis

John D. Rioux, Ramnik J. Xavier, Kent D. Taylor, Mark S. Silverberg, Philippe Goyette, Alan Huett, Todd Green, Petric Kuballa, M. Michael Barmada, Lisa Datta, Yin Yao Shugart, Anne M. Griffiths, Stephan R. Targan, Andrew F. Ippoliti, Edmond Jean Bernard, Ling Mei, Dan L. Nicolae, Miguel Regueiro, L. Philip Schumm, A. Hillary SteinhartJerome I. Rotter, Richard H. Duerr, Judy H. Cho, Mark J. Daly, Steven R. Brant

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)596-604
Number of pages9
JournalNature Genetics
Volume39
Issue number5
DOIs
StatePublished - May 2007

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Genome-Wide Association Study
Autophagy
Crohn Disease
Ileal Diseases
Gene Knockdown Techniques
Intergenic DNA
Salmonella typhimurium
Epithelial Cells
Cell Line
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., ... Brant, S. R. (2007). Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genetics, 39(5), 596-604. https://doi.org/10.1038/ng2032

Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. / Rioux, John D.; Xavier, Ramnik J.; Taylor, Kent D.; Silverberg, Mark S.; Goyette, Philippe; Huett, Alan; Green, Todd; Kuballa, Petric; Barmada, M. Michael; Datta, Lisa; Shugart, Yin Yao; Griffiths, Anne M.; Targan, Stephan R.; Ippoliti, Andrew F.; Bernard, Edmond Jean; Mei, Ling; Nicolae, Dan L.; Regueiro, Miguel; Schumm, L. Philip; Steinhart, A. Hillary; Rotter, Jerome I.; Duerr, Richard H.; Cho, Judy H.; Daly, Mark J.; Brant, Steven R.

In: Nature Genetics, Vol. 39, No. 5, 05.2007, p. 596-604.

Research output: Contribution to journalArticle

Rioux, JD, Xavier, RJ, Taylor, KD, Silverberg, MS, Goyette, P, Huett, A, Green, T, Kuballa, P, Barmada, MM, Datta, L, Shugart, YY, Griffiths, AM, Targan, SR, Ippoliti, AF, Bernard, EJ, Mei, L, Nicolae, DL, Regueiro, M, Schumm, LP, Steinhart, AH, Rotter, JI, Duerr, RH, Cho, JH, Daly, MJ & Brant, SR 2007, 'Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis', Nature Genetics, vol. 39, no. 5, pp. 596-604. https://doi.org/10.1038/ng2032
Rioux, John D. ; Xavier, Ramnik J. ; Taylor, Kent D. ; Silverberg, Mark S. ; Goyette, Philippe ; Huett, Alan ; Green, Todd ; Kuballa, Petric ; Barmada, M. Michael ; Datta, Lisa ; Shugart, Yin Yao ; Griffiths, Anne M. ; Targan, Stephan R. ; Ippoliti, Andrew F. ; Bernard, Edmond Jean ; Mei, Ling ; Nicolae, Dan L. ; Regueiro, Miguel ; Schumm, L. Philip ; Steinhart, A. Hillary ; Rotter, Jerome I. ; Duerr, Richard H. ; Cho, Judy H. ; Daly, Mark J. ; Brant, Steven R. / Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. In: Nature Genetics. 2007 ; Vol. 39, No. 5. pp. 596-604.
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