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'Amato; 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; Jonathan N W N Barker; Ole A Andreassen; Dermot P McGovern; Tom H Karlsen; Jeffrey C Barrett; Miles Parkes; Matthew A Brown; Andre Franke; International IBD Genetics Consortium (IIBDGC)

doi:10.1038/ng.3528

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, International IBD Genetics Consortium (IIBDGC)

292 Citations (Scopus)

Abstract

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 language	English
Journal	Nature Genetics
Volume	48
Issue number	5
Pages (from-to)	510-521
Number of pages	12
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3528
Publication status	Published - 1 May 2016

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Ellinghaus, D., Jostins, L., Spain, S. L., Cortes, A., Bethune, J., Han, B., Park, Y. R., Raychaudhuri, S., Pouget, J. G., Hübenthal, M., Folseraas, T., Wang, Y., Esko, T., Metspalu, A., Westra, H-J., Franke, L., Pers, T. H., Weersma, R. K., Collij, V., ... International IBD Genetics Consortium (IIBDGC) (2016). Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. Nature Genetics, 48(5), 510-521. https://doi.org/10.1038/ng.3528

Ellinghaus, D, Jostins, L, Spain, SL, Cortes, A, Bethune, J, Han, B, Park, YR, Raychaudhuri, S, Pouget, JG, Hübenthal, M, Folseraas, T, Wang, Y, Esko, T, Metspalu, A, Westra, H-J, Franke, L, Pers, TH, Weersma, RK, Collij, V, D'Amato, M, Halfvarson, J, Jensen, AB, Lieb, W, Degenhardt, F, Forstner, AJ, Hofmann, A, Schreiber, S, Mrowietz, U, Juran, BD, Lazaridis, KN, Brunak, S, Dale, AM, Trembath, RC, Weidinger, S, Weichenthal, M, Ellinghaus, E, Elder, JT, Barker, JNWN, Andreassen, OA, McGovern, DP, Karlsen, TH, Barrett, JC, Parkes, M, Brown, MA, Franke, A & International IBD Genetics Consortium (IIBDGC) 2016, 'Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci', Nature Genetics, vol. 48, no. 5, pp. 510-521. https://doi.org/10.1038/ng.3528

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

abstract = "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.",

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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 - 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

AU - International IBD Genetics Consortium (IIBDGC)

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.

U2 - 10.1038/ng.3528

DO - 10.1038/ng.3528

M3 - Journal article

C2 - 26974007

SN - 1061-4036

VL - 48

SP - 510

EP - 521

JO - Nature: New biology

JF - Nature: New biology

IS - 5

ER -

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

Abstract

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