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