Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2012 Nov 1;491(7422):119-24.
doi: 10.1038/nature11582.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Luke Jostins  1 , Stephan Ripke, Rinse K Weersma, Richard H Duerr, Dermot P McGovern, Ken Y Hui, James C Lee, L Philip Schumm, Yashoda Sharma, Carl A Anderson, Jonah Essers, Mitja Mitrovic, Kaida Ning, Isabelle Cleynen, Emilie Theatre, Sarah L Spain, Soumya Raychaudhuri, Philippe Goyette, Zhi Wei, Clara Abraham, Jean-Paul Achkar, Tariq Ahmad, Leila Amininejad, Ashwin N Ananthakrishnan, Vibeke Andersen, Jane M Andrews, Leonard Baidoo, Tobias Balschun, Peter A Bampton, Alain Bitton, Gabrielle Boucher, Stephan Brand, Carsten Büning, Ariella Cohain, Sven Cichon, Mauro D'Amato, Dirk De Jong, Kathy L Devaney, Marla Dubinsky, Cathryn Edwards, David Ellinghaus, Lynnette R Ferguson, Denis Franchimont, Karin Fransen, Richard Gearry, Michel Georges, Christian Gieger, Jürgen Glas, Talin Haritunians, Ailsa Hart, Chris Hawkey, Matija Hedl, Xinli Hu, Tom H Karlsen, Limas Kupcinskas, Subra Kugathasan, Anna Latiano, Debby Laukens, Ian C Lawrance, Charlie W Lees, Edouard Louis, Gillian Mahy, John Mansfield, Angharad R Morgan, Craig Mowat, William Newman, Orazio Palmieri, Cyriel Y Ponsioen, Uros Potocnik, Natalie J Prescott, Miguel Regueiro, Jerome I Rotter, Richard K Russell, Jeremy D Sanderson, Miquel Sans, Jack Satsangi, Stefan Schreiber, Lisa A Simms, Jurgita Sventoraityte, Stephan R Targan, Kent D Taylor, Mark Tremelling, Hein W Verspaget, Martine De Vos, Cisca Wijmenga, David C Wilson, Juliane Winkelmann, Ramnik J Xavier, Sebastian Zeissig, Bin Zhang, Clarence K Zhang, Hongyu Zhao; International IBD Genetics Consortium (IIBDGC); Mark S Silverberg, Vito Annese, Hakon Hakonarson, Steven R Brant, Graham Radford-Smith, Christopher G Mathew, John D Rioux, Eric E Schadt, Mark J Daly, Andre Franke, Miles Parkes, Severine Vermeire, Jeffrey C Barrett, Judy H Cho
Collaborators, Affiliations
Meta-Analysis

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Luke Jostins et al. Nature. .

Abstract

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

PubMed Disclaimer

Figures

Figure 1
Figure 1. The IBD genome
A) Variance explained by the 163 IBD loci. Each bar, ordered by genomic position, represents an independent locus. The width of the bar is proportional to the variance explained by that locus in CD and UC. Bars are connected together if they are identified as being associated with both CD and UC. Loci are labeled if they explain more than 1% of the total variance explained by all loci for that phenotype. B) The 193 independent signals, plotted by total IBD odds ratio and phenotype specificity (measured by the odds ratio of CD relative to UC), and colored by their IBD phenotype classification from Table 1. Note that many loci (e.g. IL23R) show very different effects in CD and UC despite being strongly associated to both. C) GRAIL network for all genes with GRAIL p < 0.05. Genes included in our previous GRAIL networks in CD and UC are shown in light blue, newly connected genes in previously identified loci in dark blue, and genes from newly associated loci in gold. The gold genes reinforce the previous network (light blue) and expand it to include dark blue genes.
Figure 2
Figure 2. Dissecting the biology of IBD
A) Number of overlapping IBD loci with other immune-mediated diseases (IMD), leprosy, and Mendelian primary immunodeficiencies (PID). Within PID, we highlight Mendelian susceptibility to mycobacterial disease (MSMD). B) Signals of selection at IBD SNPs, from strongest balancing on the left to strongest directional on the right. The grey curve shows the 95% confidence interval for randomly chosen frequency-matched SNPs, illustrating our overall enrichment (p = 5.5 × 10-6), while the dashed line represents the Bonferroni significance threshold. SNPs highlighted in red are annotated as involved in regulation of IL17 production, a key IBD functional term related to bacterial defense, and are enriched for balancing selection. C) Evidence of enrichment in IBD loci of differentially expressed genes from various immune tissues. Each bar represents the empirical p-value in a single tissue, and the colours represent different cell type groupings. The dashed line is Bonferroni-corrected significance for the number of tissues tested. D) NOD2-focused cluster of the IBD causal subnetwork. Pink genes are in IBD associated loci, blue are not. Arrows indicate inferred causal direction of regulation of expression.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Molodecky NA, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46–54. - PubMed
    1. Anderson CA, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet. 2011;43:246–252. - PMC - PubMed
    1. Franke A, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42:1118–1125. - PMC - PubMed
    1. Khor BGA, Xavier RJ. Genetics pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–317. - PMC - PubMed
    1. Cho JH, Gregersen PK. Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med. 2011;365:1612–1623. - PubMed

Publication types

MeSH terms

Grants and funding

  NODES
Association 9
INTERN 1
Note 1
twitter 2