GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways

López-Isac E, Acosta-Herrera M, Kerick M, Assassi S, Satpathy AT, Granja J, Mumbach MR, Beretta L, Simeón CP, Carreira P, Ortego-Centeno N, Castellvi I, Bossini-Castillo L, Carmona FD, Orozco G, Hunzelmann N, Distler J, Franke A, Lunardi C, Moroncini G, Gabrielli A, de Vries-Bouwstra J, Wijmenga C, Koeleman BP, Nordin A, Padyukov L, Hoffmann-Vold AM, Lie B, Ríos R, Callejas JL, Vargas-Hitos JA, García-Portales R, Camps MT, Fernández-Nebro A, González-Escribano MF, García-Hernández FJ, Castillo MJ, Aguirre MA, Gómez-Gracia I, Fernández-Gutiérrez B, Rodríguez-Rodríguez L, García de la Peña P, Vicente E, Andreu JL, Fernández de Castro M, López-Longo FJ, Martínez L, Fonollosa , Guillén A, Espinosa G, Tolosa C, Pros A, Rodríguez-Carballeira M, Narváez FJ, Rubio-Rivas M, Ortiz-Santamaría , Madroñero AB, González-Gay MA, Díaz B, Trapiella L, Sousa A, Egurbide MV, Fanlo-Mateo P, Sáez-Comet L, Díaz F, Hernández , Beltrán E, Román-Ivorra JA, Grau E, Alegre-Sancho JJ, Freire M, Blanco-García FJ, Oreiro N, Witte T, Kreuter A, Riemekasten G, Airó P, Magro C, Voskuyl AE, Vonk MC, Hesselstrand R, Proudman S, Stevens W, Nikpour M, Zochling J, Sahhar J, Roddy J, Nash P, Tymms K, Rischmueller M, Lester S, Vyse T, Herrick AL, Worthington J, Denton CP, Allanore Y, Brown MA, Radstake TR, Fonseca C, Chang HY, Mayes MD, Martin J (2019)


Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 10

Article Number: 4955

Journal Issue: 1

DOI: 10.1038/s41467-019-12760-y

Abstract

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Authors with CRIS profile

Involved external institutions

Hospital Universitario San Cecilio ES Spain (ES) Institute of Parasitology and Biomedicine López-Neyra / Instituto de Parasitología y Biomedicina "López - Neyra" ES Spain (ES) Stanford University US United States (USA) (US) Hospital Universitario 12 de Octubre ES Spain (ES) Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico IT Italy (IT) Hospital General de Granollers ES Spain (ES) Ruhr-Universität Bochum (RUB) DE Germany (DE) Leiden University Medical Center NL Netherlands (NL) Hospital Universitario Puerta de Hierro - Majadahonda ES Spain (ES) Hospital Universitario de Canarias ES Spain (ES) University of A Coruña / Universidade da Coruña ES Spain (ES) Hospital del Mar ES Spain (ES) Universidad Autónoma de Madrid (UAM) ES Spain (ES) Karolinska University Hospital / Karolinska Universitetssjukhuset SE Sweden (SE) Hospital General Universitario Gregorio Marañón ES Spain (ES) Universidad de Granada ES Spain (ES) Hospital Universitario Dr. Peset Aleixandre ES Spain (ES) Hospital Universitario y Politécnico de La Fe ES Spain (ES) Bellvitge University Hospital / Hospital Universitari de Bellvitge ES Spain (ES) Hospitales Universitarios Virgen Macarena y Virgen del Rocío ES Spain (ES) Christian-Albrechts-Universität zu Kiel DE Germany (DE) Complejo Hospitalario Universitario de Vigo (CHUVI) ES Spain (ES) Central University Hospital of Asturias ES Spain (ES) Hospital Universitario Reina Sofía de Córdoba Edificio IMIBIC ES Spain (ES) UCL Medical School GB United Kingdom (GB) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra NL Netherlands (NL) University of Manchester GB United Kingdom (GB) Lund University / Lunds universitet SE Sweden (SE) Royal Perth Hospital AU Australia (AU) University of Tasmania (UTAS) AU Australia (AU) Royal Adelaide Hospital AU Australia (AU) King’s College London GB United Kingdom (GB) St Vincent's Hospital AU Australia (AU) The Queen Elizabeth Hospital AU Australia (AU) University of Groningen / Rijksuniversiteit Groningen NL Netherlands (NL) Complejo Hospitalario de Navarra - Hospital de Navarra ES Spain (ES) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet NO Norway (NO) Wellcome Trust Sanger Institute - Genome Research Limited GB United Kingdom (GB) Università Politecnica delle Marche (UNIVPM) / Marche Polytechnic University IT Italy (IT) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron ES Spain (ES) Hospital Universitario Miguel Servet ES Spain (ES) University of Paris 5 - René Descartes / Université Paris V René Descartes FR France (FR) Queensland University of Technology (QUT) AU Australia (AU) Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia IT Italy (IT) The University of Melbourne AU Australia (AU) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Hospital General Universitari de València ES Spain (ES) MonashHeart (formerly: Cardiology, Monash Medical Centre) AU Australia (AU) Hospital General San Jorge ES Spain (ES) University of Texas Health Science Center at Houston (UTHealth) US United States (USA) (US) Universität zu Lübeck DE Germany (DE) Hospital Parc Tauli ES Spain (ES) Universidad de Cantabria (UC) ES Spain (ES) Complejo Hospitalario Universitario de Granada ES Spain (ES) Hospital Clínic de Barcelona ES Spain (ES) Canberra Rheumatology AU Australia (AU) Osakidetza ES Spain (ES) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Hospital de la Santa Creu i Sant Pau ES Spain (ES) Hospital Universitario Virgen de la Victoria ES Spain (ES) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Universität zu Köln DE Germany (DE) University of Verona / Università degli Studi di Verona IT Italy (IT)

How to cite

APA:

López-Isac, E., Acosta-Herrera, M., Kerick, M., Assassi, S., Satpathy, A.T., Granja, J.,... Martin, J. (2019). GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways. Nature Communications, 10(1). https://doi.org/10.1038/s41467-019-12760-y

MLA:

López-Isac, Elena, et al. "GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways." Nature Communications 10.1 (2019).

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