GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
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Published:2019-10-31
Issue:1
Volume:10
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
López-Isac Elena, , Acosta-Herrera Marialbert, Kerick Martin, Assassi Shervin, Satpathy Ansuman T.ORCID, Granja Jeffrey, Mumbach Maxwell R., Beretta Lorenzo, Simeón Carmen P., Carreira Patricia, Ortego-Centeno Norberto, Castellvi Ivan, Bossini-Castillo Lara, Carmona F. DavidORCID, Orozco GiselaORCID, Hunzelmann Nicolas, Distler Jörg H. W., Franke AndreORCID, Lunardi Claudio, Moroncini Gianluca, Gabrielli Armando, de Vries-Bouwstra Jeska, Wijmenga Cisca, Koeleman Bobby P. C., Nordin Annika, Padyukov LeonidORCID, Hoffmann-Vold Anna-Maria, Lie Benedicte, Proudman Susanna, Stevens Wendy, Nikpour Mandana, Vyse TimothyORCID, Herrick Ariane L., Worthington Jane, Denton Christopher P., Allanore YannickORCID, Brown Matthew A.ORCID, Radstake Timothy R. D. J., Fonseca Carmen, Chang Howard Y.ORCID, Mayes Maureen D.ORCID, Martin Javier,
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference65 articles.
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