Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci

David Ellinghaus*, Luke Jostins, Sarah L. Spain, Adrian Cortes, Jörn Bethune, Buhm Han, Yu Rang Park, Soumya Raychaudhuri, Jennie G. Pouget, Matthias Hübenthal, Trine Folseraas, Yunpeng Wang, Tonu Esko, Andres Metspalu, Harm Jan Westra, Lude Franke, Tune H. Pers, Rinse K. Weersma, Valerie Collij, Mauro D'AmatoJonas Halfvarson, Anders Boeck Jensen, Wolfgang Lieb, Franziska Degenhardt, Andreas J. Forstner, Andrea Hofmann, Stefan Schreiber, Ulrich Mrowietz, Brian D. Juran, Konstantinos N. Lazaridis, SØren Brunak, Anders M. Dale, Richard C. Trembath, Stephan Weidinger, Michael Weichenthal, Eva Ellinghaus, James T. Elder, Jonathan N W N Barker, Ole A. Andreassen, Dermot P. McGovern, Tom H. Karlsen, Jeffrey C. Barrett, Miles Parkes, Matthew A. Brown, Andre Franke

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

512 Citations (Scopus)
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We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

Original languageEnglish
Pages (from-to)510-518
Number of pages9
JournalNature Genetics
Issue number5
Early online date14 Mar 2016
Publication statusPublished - May 2016


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