A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease
David González‐Serna, Eguzkine Ochoa, Elena López‐Isac, Antonio Julià, Frauke Degenhardt, Norberto Ortego‐Centeno, Timothy R. D. J. Radstake, André Franke, Sara Marsal, Maureen D. Mayes, Javier Martı́n, Ana Márquez, Shervin Assassi, Xiaodong Zhou, Filemon K. Tan, Frank C. Arnett, John D. Reveille, Olga Y. Gorlova, Wei V. Chen, Binwu Ying, Peter K. Gregersen, Annette T. Lee, Alexandre E. Voskuyl, Jeska de Vries‐Bouwstra, César Magro‐Checa, Jasper Broen, Bobby P. C. Koeleman, Carmen Pilar Simeón‐Aznar, V Fonollosa, Alfredo Guillén, Patrícia Carreira, I. Castellví, Miguel Á. González‐Gay, Raquel Ríos, José Luís Callejas-Rubio, José Antonio Vargas‐Hitos, Rosa García-Portales, María Teresa Camps, Antonio Fernández‐Nebro, María Francisca González‐Escribano, Francisco José García Hernández, Ma. Jesús Castillo, M. Á. Aguirre, Inmaculada Gómez-Gracia, Luis Rodríguez‐Rodríguez, Benjamín Fernández‐Gutiérrez, Paloma García de la Peña, Esther Vicente, José Luís Andreu, M. Fernández Castro, Francisco Javier López-Longo, Lusiana Martínez, Gerard Espinosa, Carlos Tolosa, A. Pros, Mónica Rodríguez‐Carballeira, Francisco Javier Narváez, Manel Rubio-Rivas, Vera Ortiz-Santamaría, Ana Belén Madroñero, Bernardino Díaz, Luis Trapiella, Adrián Sousa, María Victoria Egurbide, P. Fanlo-Mateo, Luís Sáez-Comet, Federico Díaz‐González, Vanesa Hernández Hernández, E. Beltrán, José Andrés Román-Ivorra, Elena Grau, Juan José Alegre Sancho, Francisco J. Blanco, N. Oreiro, M. Freire, Alejandro Balsa, Ana M. Ortiz, Nicolas Hunzelmann, Gabriela Riemekasten, Jörg H. W. Distler, Torsten Witte, Paolo Airó, Lorenzo Beretta, Alessandro Santaniello, Chiara Bellocchi, C. Lunardi, Gianluca Moroncini, Armando Gabrielli
Abstract
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.