TY - JOUR
T1 - A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease
AU - Scleroderma Genetic Consortium
AU - González-Serna, David
AU - Ochoa, Eguzkine
AU - López-Isac, Elena
AU - Julià, Antonio
AU - Degenhardt, Frauke
AU - Ortego-Centeno, Norberto
AU - Radstake, Timothy R.D.J.
AU - Franke, Andre
AU - Marsal, Sara
AU - Mayes, Maureen D.
AU - Martín, Javier
AU - Márquez, Ana
AU - Assassi, Shervin
AU - Zhou, Xiaodong
AU - Tan, Filemon K.
AU - Arnett, Frank C.
AU - Reveille, John D.
AU - Gorlova, Olga
AU - Chen, Wei V.
AU - Ying, Jun
AU - Gregersen, Peter K.
AU - Lee, Annette T.
AU - Voskuyl, Alexandre E.
AU - de Vries-Bouwstra, Jeska
AU - Magro-Checa, Cesar
AU - Broen, Jasper
AU - Koeleman, Bobby P.C.
AU - Simeón, Carmen P.
AU - Fonollosa, Vicente
AU - Guillén, Alfredo
AU - Carreira, Patricia
AU - Castellví, Iván
AU - González-Gay, Miguel A.
AU - Ríos, Raquel
AU - Callejas-Rubio, Jose Luis
AU - Vargas-Hitos, José A.
AU - García-Portales, Rosa
AU - Camps, María Teresa
AU - Fernández-Nebro, Antonio
AU - González-Escribano, María F.
AU - García-Hernández, Francisco José
AU - Castillo, Ma Jesús
AU - Aguirre, Ma Ángeles
AU - Gómez-Gracia, Inmaculada
AU - Rodríguez-Rodríguez, Luis
AU - Fernández-Gutiérrez, Benjamín
AU - de la Peña, Paloma García
AU - Vicente, Esther
AU - Andreu, José Luis
AU - Riemekasten, Gabriela
N1 - Funding Information:
We thank Sofia Vargas and Gema Robledo for her excellent technical assistance and all the patients and control donors for their essential collaboration. We thank WTCCC (Welcome Trust Case Control Consortium) for the access to GWAS data of Crohn’s disease patients and healthy controls, Banco Nacional de ADN (University of Salamanca, Spain) who supplied part of the control DNA samples, and dbGap for granting access to the IBD Genetics Consortium (IBDGC) Crohn’s Disease GWAS data (phs000130.v1.p1). The IBDGC Crohn’s Disease Genome-Wide Association Study was conducted by the IBDGC Investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). This manuscript was not prepared in collaboration with Investigators of the IBDGC Crohn’s Disease Genome-Wide Association Study and does not necessarily reflect the opinions or views of the IBDGC Crohn’s Disease Genome-Wide Association Study, the NIDDK Central Repositories, or the NIDDK. This work was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-66761-P; IPT-010000-2010-36, cofunded by the European Regional Development Fund), Consejería de Innovación, Ciencia y Tecnología, Junta de Andalucía (Spain) (P12-BIO-1395) and the Cooperative Research Thematic Network (RETICS) programme (RD16/0012/0013) (RIER) from Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Economy, Industry and Competitiveness). AM is recipient of a Miguel Servet fellowship (CP17/00008) from ISCIII (Spanish Ministry of Economy, Industry and Competitiveness). DGS was supported by the Spanish Ministry of Economy and Competitiveness through the FPI programme (SAF2015-66761-P). This work is part of the Doctoral Thesis “Bases Genéticas de la Esclerosis Sistémica: Integrando Genómica y Transcriptómica”.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/5
Y1 - 2020/2/5
N2 - Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.
AB - Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn’s disease (CD), some of which confer susceptibility to both diseases. In order to identify new risk loci shared between these two immune-mediated disorders, we performed a cross-disease meta-analysis including GWAS data from 5,734 SSc patients, 4,588 CD patients and 14,568 controls of European origin. We identified 4 new loci shared between SSc and CD, IL12RB2, IRF1/SLC22A5, STAT3 and an intergenic locus at 6p21.31. Pleiotropic variants within these loci showed opposite allelic effects in the two analysed diseases and all of them showed a significant effect on gene expression. In addition, an enrichment in the IL-12 family and type I interferon signaling pathways was observed among the set of SSc-CD common genetic risk loci. In conclusion, through the first cross-disease meta-analysis of SSc and CD, we identified genetic variants with pleiotropic effects on two clinically distinct immune-mediated disorders. The fact that all these pleiotropic SNPs have opposite allelic effects in SSc and CD reveals the complexity of the molecular mechanisms by which polymorphisms affect diseases.
UR - http://www.scopus.com/inward/record.url?scp=85079032908&partnerID=8YFLogxK
U2 - 10.1038/s41598-020-58741-w
DO - 10.1038/s41598-020-58741-w
M3 - Journal articles
C2 - 32024964
AN - SCOPUS:85079032908
SN - 2045-2322
VL - 10
SP - 1862
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 1862
ER -
