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 Wu; 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.

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. © 2007 Nature Publishing Group.

Citation

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., …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

• Journal Article Type: Article
• Acceptance Date: Mar 26, 2007
• Online Publication Date: Apr 15, 2007
• Publication Date: 2007-05
• Deposit Date: Aug 15, 2022
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 39
• Issue: 5
• Pages: 596-604
• DOI: https://doi.org/10.1038/ng2032
• Public URL: https://nottingham-repository.worktribe.com/output/3181886
• Publisher URL: https://www.nature.com/articles/ng2032