TY - JOUR
T1 - Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci
AU - Ellinghaus, David
AU - Jostins, Luke
AU - Spain, Sarah L.
AU - Cortes, Adrian
AU - Bethune, Jörn
AU - Han, Buhm
AU - Park, Yu Rang
AU - Raychaudhuri, Soumya
AU - Pouget, Jennie G.
AU - Hübenthal, Matthias
AU - Folseraas, Trine
AU - Wang, Yunpeng
AU - Esko, Tonu
AU - Metspalu, Andres
AU - Westra, Harm Jan
AU - Franke, Lude
AU - Pers, Tune H.
AU - Weersma, Rinse K.
AU - Collij, Valerie
AU - D'Amato, Mauro
AU - Halfvarson, Jonas
AU - Jensen, Anders Boeck
AU - Lieb, Wolfgang
AU - Degenhardt, Franziska
AU - Forstner, Andreas J.
AU - Hofmann, Andrea
AU - International Inflammatory Bowel Disease Genetics Consortium
AU - Lawrance, Ian
AU - International Genetics of Ankylosing Spondylitis Consortium
AU - International PSC Study Group
AU - Genetic Analysis of Psoriasis Consortium
AU - Psoriasis Association Genetics Extension
AU - Schreiber, Stefan
AU - Mrowietz, Ulrich
AU - Juran, Brian D.
AU - Lazaridis, Konstantinos N.
AU - Brunak, SØren
AU - Dale, Anders M.
AU - Trembath, Richard C.
AU - Weidinger, Stephan
AU - Weichenthal, Michael
AU - Ellinghaus, Eva
AU - Elder, James T.
AU - Barker, Jonathan N.W.N.
AU - Andreassen, Ole A.
AU - McGovern, Dermot P.
AU - Karlsen, Tom H.
AU - Barrett, Jeffrey C.
AU - Parkes, Miles
AU - Brown, Matthew A.
AU - Franke, Andre
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84964772502&partnerID=8YFLogxK
U2 - 10.1038/ng.3528
DO - 10.1038/ng.3528
M3 - Article
C2 - 26974007
AN - SCOPUS:84964772502
SN - 1061-4036
VL - 48
SP - 510
EP - 518
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -