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

Publication

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

Journal Paper/Review - Nov 1, 2012

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

Citation

Kupcinskas L, Potocnik U, Prescott N, Regueiro M, Rotter J, Russell R, Sanderson J, Sans M, Satsangi J, Schreiber S, Simms L, Sventoraityte J, Ponsioen C, Palmieri O, Kugathasan S, Latiano A, Laukens D, Lawrance I, Lees C, Louis E, Mahy G, Mansfield J, Morgan A, Mowat C, Newman W, Targan S, Taylor K, Tremelling M, Hakonarson H, Brant S, Radford-Smith G, Mathew C, Rioux J, Schadt E, Daly M, Franke A, Parkes M, Vermeire S, Barrett J, Annese V, Silverberg M, Verspaget H, De Vos M, Wijmenga C, Wilson D, Winkelmann J, Xavier R, Zeissig S, Zhang B, Zhang C, Zhao H, Cho J, Karlsen T, Jostins L, Theatre E, Spain S, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar J, Ahmad T, Amininejad L, Ananthakrishnan A, Andersen V, Cleynen I, Ning K, Ripke S, Weersma R, Duerr R, McGovern D, Hui K, Lee J, Schumm L, Sharma Y, Anderson C, Essers J, Mitrovic M, Andrews J, Baidoo L, Balschun T, Ferguson L, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Ellinghaus D, Edwards C, Bampton P, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney K, Dubinsky M, Hu X. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491:119-24.

Type

Journal Paper/Review (English)

Journal

Nature 2012; 491

Publication Date

Nov 1, 2012

Issn Electronic

1476-4687

Pages

119-24

Brief description/objective

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.