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; Andre Franke; Sara Marsal; Maureen D. Mayes; Javier Martín; Ana Márquez; Shervin Assassi; Xiaodong Zhou; Filemon K. Tan; Frank C. Arnett; John D. Reveille; Olga Gorlova; Wei V. Chen; Jun Ying; Peter K. Gregersen; Annette T. Lee; Alexandre E. Voskuyl; Jeska de Vries-Bouwstra; Cesar Magro-Checa; Jasper Broen; Bobby P.C. Koeleman; Carmen P. Simeón; Vicente Fonollosa; Alfredo Guillén; Patricia Carreira; Iván Castellví; Miguel A. González-Gay; Raquel Ríos; Jose Luis Callejas-Rubio; José A. Vargas-Hitos; Rosa García-Portales; María Teresa Camps; Antonio Fernández-Nebro; María F. González-Escribano; Francisco José García-Hernández; Ma Jesús Castillo; Ma Ángeles Aguirre; Inmaculada Gómez-Gracia; Luis Rodríguez-Rodríguez; Benjamín Fernández-Gutiérrez; Paloma García de la Peña; Esther Vicente; José Luis Andreu; Mónica Fernández de Castro; Francisco Javier López-Longo; Lina Martínez; Gerard Espinosa; Carlos Tolosa; Anna 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; Patricia Fanlo-Mateo; Luis Sáez-Comet; Federico Díaz-González; Vanesa Hernández; Emma Beltrán; José Andrés Román-Ivorra; Elena Grau; Juan José Alegre-Sancho; Francisco J. Blanco-García; Natividad Oreiro; Mayka Freire; Alejandro Balsa; Ana M. Ortiz; Nicolas Hunzelmann; Gabriela Riemekasten; Jörg H.W. Distler; Torsten Witte; Paolo Airó; Lorenzo Beretta; Alessandro Santaniello; Chiara Bellocchi; Claudio Lunardi; Gianluca Moroncini; Armando Gabrielli; Scleroderma Genetic Consortium

doi:10.1038/s41598-020-58741-w

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, Andre Franke, Sara Marsal, Maureen D. Mayes, Javier Martín, Ana Márquez^*, Shervin Assassi, Xiaodong Zhou, Filemon K. Tan, Frank C. Arnett, John D. Reveille, Olga Gorlova, Wei V. Chen, Jun YingPeter K. Gregersen, Annette T. Lee, Alexandre E. Voskuyl, Jeska de Vries-Bouwstra, Cesar Magro-Checa, Jasper Broen, Bobby P.C. Koeleman, Carmen P. Simeón, Vicente Fonollosa, Alfredo Guillén, Patricia Carreira, Iván Castellví, Miguel A. González-Gay, Raquel Ríos, Jose Luis Callejas-Rubio, José A. Vargas-Hitos, Rosa García-Portales, María Teresa Camps, Antonio Fernández-Nebro, María F. González-Escribano, Francisco José García-Hernández, Ma Jesús Castillo, Ma Ángeles Aguirre, Inmaculada Gómez-Gracia, Luis Rodríguez-Rodríguez, Benjamín Fernández-Gutiérrez, Paloma García de la Peña, Esther Vicente, José Luis Andreu, Mónica Fernández de Castro, Francisco Javier López-Longo, Lina Martínez, Gerard Espinosa, Carlos Tolosa, Anna 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, Patricia Fanlo-Mateo, Luis Sáez-Comet, Federico Díaz-González, Vanesa Hernández, Emma Beltrán, José Andrés Román-Ivorra, Elena Grau, Juan José Alegre-Sancho, Francisco J. Blanco-García, Natividad Oreiro, Mayka Freire, Alejandro Balsa, Ana M. Ortiz, Nicolas Hunzelmann, Gabriela Riemekasten, Jörg H.W. Distler, Torsten Witte, Paolo Airó, Lorenzo Beretta, Alessandro Santaniello, Chiara Bellocchi, Claudio Lunardi, Gianluca Moroncini, Armando Gabrielli, Scleroderma Genetic Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	1862
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-58741-w
Publication status	Published - 1 Dec 2020

Access to Document

10.1038/s41598-020-58741-w

Cite this

González-Serna, D., Ochoa, E., López-Isac, E., Julià, A., Degenhardt, F., Ortego-Centeno, N., Radstake, T. R. D. J., Franke, A., Marsal, S., Mayes, M. D., Martín, J., Márquez, A., Assassi, S., Zhou, X., Tan, F. K., Arnett, F. C., Reveille, J. D., Gorlova, O., Chen, W. V., ... Scleroderma Genetic Consortium (2020). A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease. Scientific Reports, 10(1), [1862]. https://doi.org/10.1038/s41598-020-58741-w

@article{093ac2ec7f914a828ea60ff19b883a89,

title = "A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn{\textquoteright}s disease",

abstract = "Genome-wide association studies (GWASs) have identified a number of genetic risk loci associated with systemic sclerosis (SSc) and Crohn{\textquoteright}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.",

author = "David Gonz{\'a}lez-Serna and Eguzkine Ochoa and Elena L{\'o}pez-Isac and Antonio Juli{\`a} and Frauke Degenhardt and Norberto Ortego-Centeno and Radstake, {Timothy R.D.J.} and Andre Franke and Sara Marsal and Mayes, {Maureen D.} and Javier Mart{\'i}n and Ana M{\'a}rquez and Shervin Assassi and Xiaodong Zhou and Tan, {Filemon K.} and Arnett, {Frank C.} and Reveille, {John D.} and Olga Gorlova and Chen, {Wei V.} and Jun Ying and Gregersen, {Peter K.} and Lee, {Annette T.} and Voskuyl, {Alexandre E.} and {de Vries-Bouwstra}, Jeska and Cesar Magro-Checa and Jasper Broen and Koeleman, {Bobby P.C.} and Sime{\'o}n, {Carmen P.} and Vicente Fonollosa and Alfredo Guill{\'e}n and Patricia Carreira and Iv{\'a}n Castellv{\'i} and Gonz{\'a}lez-Gay, {Miguel A.} and Raquel R{\'i}os and Callejas-Rubio, {Jose Luis} and Vargas-Hitos, {Jos{\'e} A.} and Rosa Garc{\'i}a-Portales and Camps, {Mar{\'i}a Teresa} and Antonio Fern{\'a}ndez-Nebro and Gonz{\'a}lez-Escribano, {Mar{\'i}a F.} and Garc{\'i}a-Hern{\'a}ndez, {Francisco Jos{\'e}} and Castillo, {Ma Jes{\'u}s} and Aguirre, {Ma {\'A}ngeles} and Inmaculada G{\'o}mez-Gracia and Luis Rodr{\'i}guez-Rodr{\'i}guez and Benjam{\'i}n Fern{\'a}ndez-Guti{\'e}rrez and {de la Pe{\~n}a}, {Paloma Garc{\'i}a} and Esther Vicente and Andreu, {Jos{\'e} Luis} and {Fern{\'a}ndez de Castro}, M{\'o}nica and L{\'o}pez-Longo, {Francisco Javier} and Lina Mart{\'i}nez and Gerard Espinosa and Carlos Tolosa and Anna Pros and M{\'o}nica Rodr{\'i}guez-Carballeira and Narv{\'a}ez, {Francisco Javier} and Manel Rubio-Rivas and Vera Ortiz-Santamar{\'i}a and Madro{\~n}ero, {Ana Bel{\'e}n} and Bernardino D{\'i}az and Luis Trapiella and Adri{\'a}n Sousa and Egurbide, {Mar{\'i}a Victoria} and Patricia Fanlo-Mateo and Luis S{\'a}ez-Comet and Federico D{\'i}az-Gonz{\'a}lez and Vanesa Hern{\'a}ndez and Emma Beltr{\'a}n and Rom{\'a}n-Ivorra, {Jos{\'e} Andr{\'e}s} and Elena Grau and Alegre-Sancho, {Juan Jos{\'e}} and Blanco-Garc{\'i}a, {Francisco J.} and Natividad Oreiro and Mayka Freire and Alejandro Balsa and Ortiz, {Ana M.} and Nicolas Hunzelmann and Gabriela Riemekasten and Distler, {J{\"o}rg H.W.} and Torsten Witte and Paolo Air{\'o} and Lorenzo Beretta and Alessandro Santaniello and Chiara Bellocchi and Claudio Lunardi and Gianluca Moroncini and Armando Gabrielli and {Scleroderma Genetic Consortium}",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41598-020-58741-w",

language = "English",

volume = "10",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

González-Serna, D, Ochoa, E, López-Isac, E, Julià, A, Degenhardt, F, Ortego-Centeno, N, Radstake, TRDJ, Franke, A, Marsal, S, Mayes, MD, Martín, J, Márquez, A, Assassi, S, Zhou, X, Tan, FK, Arnett, FC, Reveille, JD, Gorlova, O, Chen, WV, Ying, J, Gregersen, PK, Lee, AT, Voskuyl, AE, de Vries-Bouwstra, J, Magro-Checa, C, Broen, J, Koeleman, BPC, Simeón, CP, Fonollosa, V, Guillén, A, Carreira, P, Castellví, I, González-Gay, MA, Ríos, R, Callejas-Rubio, JL, Vargas-Hitos, JA, García-Portales, R, Camps, MT, Fernández-Nebro, A, González-Escribano, MF, García-Hernández, FJ, Castillo, MJ, Aguirre, MÁ, Gómez-Gracia, I, Rodríguez-Rodríguez, L, Fernández-Gutiérrez, B, de la Peña, PG, Vicente, E, Andreu, JL, Fernández de Castro, M, López-Longo, FJ, Martínez, L, Espinosa, G, Tolosa, C, Pros, A, Rodríguez-Carballeira, M, Narváez, FJ, Rubio-Rivas, M, Ortiz-Santamaría, V, Madroñero, AB, Díaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Sáez-Comet, L, Díaz-González, F, Hernández, V, Beltrán, E, Román-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Blanco-García, FJ, Oreiro, N, Freire, M, Balsa, A, Ortiz, AM, Hunzelmann, N, Riemekasten, G, Distler, JHW, Witte, T, Airó, P, Beretta, L, Santaniello, A, Bellocchi, C, Lunardi, C, Moroncini, G, Gabrielli, A & Scleroderma Genetic Consortium 2020, 'A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease', Scientific Reports, vol. 10, no. 1, 1862. https://doi.org/10.1038/s41598-020-58741-w

TY - JOUR

T1 - A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease

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 - Fernández de Castro, Mónica

AU - López-Longo, Francisco Javier

AU - Martínez, Lina

AU - Espinosa, Gerard

AU - Tolosa, Carlos

AU - Pros, Anna

AU - Rodríguez-Carballeira, Mónica

AU - Narváez, Francisco Javier

AU - Rubio-Rivas, Manel

AU - Ortiz-Santamaría, Vera

AU - Madroñero, Ana Belén

AU - Díaz, Bernardino

AU - Trapiella, Luis

AU - Sousa, Adrián

AU - Egurbide, María Victoria

AU - Fanlo-Mateo, Patricia

AU - Sáez-Comet, Luis

AU - Díaz-González, Federico

AU - Hernández, Vanesa

AU - Beltrán, Emma

AU - Román-Ivorra, José Andrés

AU - Grau, Elena

AU - Alegre-Sancho, Juan José

AU - Blanco-García, Francisco J.

AU - Oreiro, Natividad

AU - Freire, Mayka

AU - Balsa, Alejandro

AU - Ortiz, Ana M.

AU - Hunzelmann, Nicolas

AU - Riemekasten, Gabriela

AU - Distler, Jörg H.W.

AU - Witte, Torsten

AU - Airó, Paolo

AU - Beretta, Lorenzo

AU - Santaniello, Alessandro

AU - Bellocchi, Chiara

AU - Lunardi, Claudio

AU - Moroncini, Gianluca

AU - Gabrielli, Armando

AU - Scleroderma Genetic Consortium

PY - 2020/12/1

Y1 - 2020/12/1

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 - Article

C2 - 32024964

AN - SCOPUS:85079032908

VL - 10

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 1862

ER -

A cross-disease meta-GWAS identifies four new susceptibility loci shared between systemic sclerosis and Crohn’s disease

Abstract

Access to Document

Other files and links

Cite this