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

2016; Nature Portfolio; Volume: 48; Issue: 5 Linguagem: Inglês

10.1038/ng.3528

1546-1718

David Ellinghaus, Luke Jostins, Sarah L. Spain, Adrián Cortés, Jörn Bethune, Buhm Han, Yu Rang Park, Soumya Raychaudhuri, Jennie G. Pouget, Matthias Hübenthal, Trine Folseraas, Yunpeng Wang, Tõnu Esko, Andres Metspalu, Harm-Jan Westra, Lude Franke, Tune H. Pers, Rinse K. Weersma, Valerie Collij, Mauro DʼAmato, Jonas 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, Juliet N. Barker, Ole A. Andreassen, Dermot McGovern, Tom H. Karlsen, Jeffrey C. Barrett, Miles Parkes, Matthew A. Brown, André Franke,

Liver Diseases and Immunity

David Ellinghaus and colleagues report a combined association analysis of five chronic inflammatory diseases. They identify 27 new associations and highlight disease-specific association patterns at shared susceptibility loci. 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.