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.

Details

Title
A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease
Author
González-Serna, David 1 ; Ochoa Eguzkine 2 ; López-Isac, Elena 1 ; Julià Antonio 3   VIAFID ORCID Logo  ; Degenhardt Frauke 4 ; Ortego-Centeno Norberto 5 ; Radstake Timothy R D J 6 ; Franke, Andre 4   VIAFID ORCID Logo  ; Marsal, Sara 3 ; Mayes, Maureen D 7   VIAFID ORCID Logo  ; Martín, Javier 1 ; Márquez, Ana 8 ; Assassi Shervin 7 ; Zhou, Xiaodong 7 ; Tan, Filemon K 7 ; Arnett, Frank C 7 ; Reveille, John D 7 ; Gorlova Olga 9 ; Chen, Wei V 9 ; Ying, Jun 9 ; Gregersen, Peter K 10 ; Lee, Annette T 10 ; Voskuyl, Alexandre E 11 ; de Vries-Bouwstra Jeska 12 ; Magro-Checa Cesar 12 ; Broen Jasper 13 ; Koeleman Bobby P C 14 ; Simeón, Carmen P 15 ; Fonollosa Vicente 15 ; Guillén Alfredo 15 ; Carreira, Patricia 16 ; Castellví Iván 17 ; González-Gay, Miguel A 18 ; Ríos, Raquel 19 ; Callejas-Rubio, Jose Luis 19 ; Vargas-Hitos, José A 20 ; García-Portales, Rosa 21 ; Camps, María Teresa 22 ; Fernández-Nebro, Antonio 23 ; González-Escribano, María F 24 ; García-Hernández, Francisco José 25 ; Castillo, Ma Jesús 25 ; Aguirre, Ma Ángeles 26 ; Gómez-Gracia Inmaculada 26 ; Rodríguez-Rodríguez, Luis 27 ; Fernández-Gutiérrez Benjamín 27 ; de la Peña Paloma García 28 ; Vicente, Esther 29 ; Andreu, José Luis 30 ; Fernández de Castro Mónica 30 ; López-Longo, Francisco Javier 31 ; Martínez Lina 31 ; Espinosa, Gerard 32 ; Tolosa, Carlos 33 ; Pros Anna 34 ; Rodríguez-Carballeira Mónica 35 ; Narváez, Francisco Javier 36 ; Rubio-Rivas, Manel 37 ; Ortiz-Santamaría, Vera 38 ; Madroñero, Ana Belén 39 ; Díaz Bernardino 40 ; Trapiella Luis 40 ; Sousa Adrián 41 ; Egurbide María Victoria 42 ; Fanlo-Mateo, Patricia 43 ; Sáez-Comet, Luis 44 ; Díaz-González Federico 45 ; Hernández Vanesa 45 ; Beltrán, Emma 46 ; Román-Ivorra, José Andrés 47 ; Grau, Elena 47 ; Alegre-Sancho, Juan José 48 ; Blanco-García, Francisco J 49 ; Oreiro Natividad 49 ; Freire Mayka 50 ; Balsa Alejandro 51 ; Ortiz, Ana M 52 ; Hunzelmann Nicolas 53 ; Riemekasten Gabriela 54 ; Distler Jörg H W 55 ; Witte Torsten 56 ; Airó Paolo 57 ; Beretta, Lorenzo 58 ; Santaniello Alessandro 58 ; Bellocchi Chiara 58 ; Lunardi, Claudio 59 ; Moroncini Gianluca 60 ; Gabrielli, Armando 60 

1  Consejo Superior de Investigaciones Científicas (CSIC), PTS, Instituto de Parasitología y Biomedicina López-Neyra, Granada, Spain (GRID:grid.418805.0) (ISNI:0000 0004 0500 8423) 
2  Consejo Superior de Investigaciones Científicas (CSIC), PTS, Instituto de Parasitología y Biomedicina López-Neyra, Granada, Spain (GRID:grid.418805.0) (ISNI:0000 0004 0500 8423); University of Cambridge, Medical Genetics department, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
3  Vall d’Hebron Research Institute, Rheumatology Research Group, Barcelona, Spain (GRID:grid.430994.3) (ISNI:0000 0004 1763 0287) 
4  Christian-Albrechts-University of Kiel, Institute of Clinical Molecular Biology, Kiel, Germany (GRID:grid.9764.c) (ISNI:0000 0001 2153 9986) 
5  Hospital Universitario San Cecilio, Granada; School of Medicine, University of Granada, Instituto de Investigación Biosanitaria ibs.GRANADA, Systemic Autoimmune Diseases Unit, Granada, Spain (GRID:grid.9764.c) 
6  University Medical Center Utrecht, Department of Rheumatology and Clinical Immunology, Utrecht, The Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
7  The University of Texas Health Science Center-Houston, Division of Rheumatology and Clinical Immunogenetics, Houston, USA (GRID:grid.267308.8) (ISNI:0000 0000 9206 2401) 
8  Consejo Superior de Investigaciones Científicas (CSIC), PTS, Instituto de Parasitología y Biomedicina López-Neyra, Granada, Spain (GRID:grid.418805.0) (ISNI:0000 0004 0500 8423); Hospital Universitario San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Systemic Autoimmune Disease Unit, Granada, Spain (GRID:grid.459499.c) 
9  The University of Texas MD Anderson Cancer Center, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
10  North Shore – Long Island Jewish Health System, The Feinstein Institute for Medical Research, Manhasset, USA (GRID:grid.416477.7) (ISNI:0000 0001 2168 3646) 
11  VU University Medical Center, Department of Rheumatology, Amsterdam, The Netherlands (GRID:grid.16872.3a) (ISNI:0000 0004 0435 165X) 
12  Leiden University Medical Center, Department of Rheumatology, Leiden, The Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978) 
13  Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); University Medical Center Utrecht, Department of Genetics, Center for Molecular Medicine, Utrecht, the Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
14  University Medical Center Utrecht, Department of Genetics, Center for Molecular Medicine, Utrecht, the Netherlands (GRID:grid.7692.a) (ISNI:0000000090126352) 
15  Hospital Universitario Vall d’Hebron, Autoimmune Diseases Unit, Department of Internal Medicine, Barcelona, Spain (GRID:grid.411083.f) (ISNI:0000 0001 0675 8654) 
16  12 de Octubre University Hospital, Reumatology Department, Madrid, Spain (GRID:grid.144756.5) (ISNI:0000 0001 1945 5329) 
17  Santa Creu i Sant Pau University Hospital, Rheumatology Unit, Barcelona, Spain (GRID:grid.144756.5) 
18  University of Cantabria, Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, IDIVAL, Santander, Spain (GRID:grid.7821.c) (ISNI:0000 0004 1770 272X) 
19  Hospital Universitario San Cecilio, Granada; School of Medicine, University of Granada, Instituto de Investigación Biosanitaria ibs.GRANADA, Systemic Autoimmune Diseases Unit, Granada, Spain (GRID:grid.7821.c) 
20  Hospital Virgen de las Nieves, Systemic Autoimmune Diseases Unit, Department of Internal Medicine, Granada, Spain (GRID:grid.411380.f) (ISNI:0000 0000 8771 3783) 
21  Hospital Virgen de la Victoria, Rheumatology Department, Málaga, Spain (GRID:grid.411062.0) (ISNI:0000 0000 9788 2492) 
22  Hospital Carlos Haya, Internal Medicine Department, Málaga, Spain (GRID:grid.411457.2) 
23  Hospital Carlos Haya, Rheumatology Department, Málaga, Spain (GRID:grid.411457.2) 
24  Hospital Universitario Virgen del Rocío (IBiS, CSIC, US), Department of Immunology, Sevilla, Spain (GRID:grid.411109.c) (ISNI:0000 0000 9542 1158) 
25  Hospital Universitario Virgen del Rocío, Department of Internal Medicine, Sevilla, Spain (GRID:grid.411109.c) (ISNI:0000 0000 9542 1158) 
26  Hospital Reina Sofía/IMIBIC, Córdoba, Spain (GRID:grid.428865.5) (ISNI:0000 0004 0445 6160) 
27  UGC de Reumatología, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain (GRID:grid.411068.a) (ISNI:0000 0001 0671 5785) 
28  Madrid Norte Sanchinarro Hospital, Rheumatology Department, Madrid, Spain (GRID:grid.411068.a) 
29  La Princesa Hospital, Department of Rheumatology, Madrid, Spain (GRID:grid.411068.a) 
30  Hospital Puerta de Hierro Majadahonda, Department of Rheumatology, Madrid, Spain (GRID:grid.73221.35) (ISNI:0000 0004 1767 8416) 
31  Hospital General Universitario Gregorio Marañón, Department of Rheumatology, Madrid, Spain (GRID:grid.410526.4) (ISNI:0000 0001 0277 7938) 
32  Hospital Clínic de Barcelona, Department of Autoimmune Diseases, Barcelona, Spain (GRID:grid.410458.c) (ISNI:0000 0000 9635 9413) 
33  Hospital Parc Tauli, Department of Internal Medicine, Sabadell, Spain (GRID:grid.414560.2) (ISNI:0000 0004 0506 7757) 
34  Hospital Del Mar, Department of Rheumatology, Barcelona, Spain (GRID:grid.411142.3) (ISNI:0000 0004 1767 8811) 
35  Hospital Universitari Mútua Terrasa, Department of Internal Medicine, Barcelona, Spain (GRID:grid.414875.b) (ISNI:0000 0004 1794 4956) 
36  Hospital Universitari de Bellvitge, Department of Rheumatology, Barcelona, Spain (GRID:grid.411129.e) (ISNI:0000 0000 8836 0780) 
37  Hospital Universitari de Bellvitge, Autoimmune Diseases Unit, Department of Internal Medicine, Barcelona, Spain (GRID:grid.411129.e) (ISNI:0000 0000 8836 0780) 
38  Hospital General de Granollers, Autoimmune Diseases Unit, Department of Rheumatology, Granollers, Spain (GRID:grid.414740.2) (ISNI:0000 0000 8569 3993) 
39  Hospital General San Jorge, Department of Internal Medicine, Huesca, Spain (GRID:grid.415076.1) (ISNI:0000 0004 1765 5935) 
40  Hospital Central de Asturias, Department of Internal Medicine, Oviedo, Spain (GRID:grid.411052.3) (ISNI:0000 0001 2176 9028) 
41  Hospital Xeral-Complexo Hospitalario Universitario de Vigo, Internal Medicine Department, Vigo, Spain (GRID:grid.411855.c) (ISNI:0000 0004 1757 0405) 
42  Hospital Universitario Cruces, Department of Internal Medicine, Barakaldo, Spain (GRID:grid.411232.7) (ISNI:0000 0004 1767 5135) 
43  Hospital Virgen del Camino, Department of Internal Medicine, Pamplona, Spain (GRID:grid.413524.5) (ISNI:0000 0000 8718 9037) 
44  Hospital Universitario Miguel Servet, Department of Internal Medicine, Zaragoza, Spain (GRID:grid.411106.3) (ISNI:0000 0000 9854 2756) 
45  Hospital Universitario de Canarias, Department of Internal Medicine, Tenerife, Spain (GRID:grid.411220.4) (ISNI:0000 0000 9826 9219) 
46  Hospital General Universitario de Valencia, Department of Rheumatology, Valencia, Spain (GRID:grid.106023.6) (ISNI:0000 0004 1770 977X) 
47  Hospital Universitari i Politecnic La Fe, Department of Rheumatology, Valencia, Spain (GRID:grid.84393.35) (ISNI:0000 0001 0360 9602) 
48  Hospital Universitari Doctor Peset, Department of Rheumatology, Valencia, Spain (GRID:grid.411289.7) (ISNI:0000 0004 1770 9825) 
49  INIBIC-Hospital Universitario A Coruña, La Coruña, Spain (GRID:grid.411066.4) (ISNI:0000 0004 1771 0279) 
50  Complexo Hospitalario Universitario de Vigo, Systemic Autoimmune Diseases and Thrombosis Unit, Department of Internal Medicine, Vigo, Spain (GRID:grid.411855.c) (ISNI:0000 0004 1757 0405) 
51  Hospital Universitario La Paz, Instituto de Investigación Sanitaria La Paz. IdiPAZ, Department of Rheumatology, Madrid, Spain (GRID:grid.81821.32) (ISNI:0000 0000 8970 9163) 
52  Hospital Universitario La Princesa, IIS-IP, Rheumatology Service, Madrid, Spain (GRID:grid.411251.2) (ISNI:0000 0004 1767 647X) 
53  University Hospital Cologne, Department of Dermatology, Cologne, Germany (GRID:grid.411097.a) (ISNI:0000 0000 8852 305X) 
54  Charité University Hospital, Berlin, and Department of Rheumatology University of Lübeck, Department of Rheumatology and Clinical Immunology, Lübeck, Germany (GRID:grid.4562.5) (ISNI:0000 0001 0057 2672) 
55  University of Erlangen-Nuremberg, Department of Internal Medicine, Institute for Clinical Immunology, Erlangen, Germany (GRID:grid.5330.5) (ISNI:0000 0001 2107 3311) 
56  University of Hannover, Hannover, Germany (GRID:grid.9122.8) (ISNI:0000 0001 2163 2777) 
57  Rheumatology and Clinical Immunology Unit, Spedali Civili, Brescia, Italy (GRID:grid.412725.7) 
58  Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy (GRID:grid.414818.0) (ISNI:0000 0004 1757 8749) 
59  Università degli Studi di Verona, Department of Medicine, Verona, Italy (GRID:grid.5611.3) (ISNI:0000 0004 1763 1124) 
60  Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy (GRID:grid.7010.6) (ISNI:0000 0001 1017 3210) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-020-58741-w
ProQuest document ID
2351473674
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.