A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease
Authors: González-Serna David , Ochoa Eguzkine , López-Isac Elena , Julià Antonio , Degenhardt Frauke , Ortego-Centeno Norberto , Radstake Timothy R. D. J. , Franke Andre , Marsal Sara , Mayes Maureen D. , Martín Javier , Márquez Ana ,   Scleroderma Genetic Consortium, Assassi Shervin , Zhou Xiaodong , Tan Filemon K. , Arnett Frank C. , Reveille John D. , Gorlova Olga , Chen Wei V. , Ying Jun , Gregersen Peter K. , Lee Annette T. , Voskuyl Alexandre E. , de Vries-Bouwstra Jeska , Magro-Checa Cesar , Broen Jasper , Koeleman Bobby P. C. , Simeón Carmen P. , Fonollosa Vicente , Guillén Alfredo , Carreira Patricia , Castellví Iván , González-Gay Miguel A. , Ríos Raquel , Callejas-Rubio Jose Luis , Vargas-Hitos José A. , García-Portales Rosa , Camps María Teresa , Fernández-Nebro Antonio , González-Escribano María F. , García-Hernández Francisco José , Castillo Ma. Jesús , Aguirre Ma. Ángeles , Gómez-Gracia Inmaculada , Rodríguez-Rodríguez Luis , Fernández-Gutiérrez Benjamín , de la Peña Paloma García , Vicente Esther , Andreu José Luis , Fernández de Castro Mónica , López-Longo Francisco Javier , Martínez Lina , Espinosa Gerard , Tolosa Carlos , Pros Anna , Rodríguez-Carballeira Mónica , Narváez Francisco Javier , Rubio-Rivas Manel , Ortiz-Santamaría Vera , Madroñero Ana Belén , Díaz Bernardino , Trapiella Luis , Sousa Adrián , Egurbide María Victoria , Fanlo-Mateo Patricia , Sáez-Comet Luis , Díaz-González Federico , Hernández Vanesa , Beltrán Emma , Román-Ivorra José Andrés , Grau Elena , Alegre-Sancho Juan José , Blanco-García Francisco J. , Oreiro Natividad , Freire Mayka , Balsa Alejandro , Ortiz Ana M. , Hunzelmann Nicolas , Riemekasten Gabriela , Distler Jörg H. W. , Witte Torsten , Airó Paolo , Beretta Lorenzo , Santaniello Alessandro , Bellocchi Chiara , Lunardi Claudio , Moroncini Gianluca , Gabrielli Armando 
Published: February 2020

AbstractGenome-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.