![]() ![]() 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. B) Signals of selection at IBD SNPs, from strongest balancing on the left to strongest directional on the right. Within PID, we highlight Mendelian susceptibility to mycobacterial disease (MSMD). The gold genes reinforce the previous network (light blue) and expand it to include dark blue genes.Ī) Number of overlapping IBD loci with other immune-mediated diseases (IMD), leprosy, and Mendelian primary immunodeficiencies (PID). 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. C) GRAIL network for all genes with GRAIL p < 0.05. IL23R) show very different effects in CD and UC despite being strongly associated to both. 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. Loci are labeled if they explain more than 1% of the total variance explained by all loci for that phenotype. Bars are connected together if they are identified as being associated with both CD and UC. The width of the bar is proportional to the variance explained by that locus in CD and UC. Each bar, ordered by genomic position, represents an independent locus. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.Ī) Variance explained by the 163 IBD loci. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. ![]() Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. 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. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. 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. 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. , 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 ChoĬrohn'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. ![]()
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