TY - JOUR
T1 - GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
AU - European Scleroderma Group†
AU - Australian Scleroderma Interest Group (ASIG)
AU - López-Isac, Elena
AU - Acosta-Herrera, Marialbert
AU - Kerick, Martin
AU - Assassi, Shervin
AU - Satpathy, Ansuman T.
AU - Granja, Jeffrey
AU - Mumbach, Maxwell R.
AU - Beretta, Lorenzo
AU - Simeón, Carmen P.
AU - Carreira, Patricia
AU - Ortego-Centeno, Norberto
AU - Castellvi, Ivan
AU - Bossini-Castillo, Lara
AU - Carmona, F. David
AU - Orozco, Gisela
AU - Hunzelmann, Nicolas
AU - Distler, Jörg H.W.
AU - Franke, Andre
AU - Lunardi, Claudio
AU - Moroncini, Gianluca
AU - Gabrielli, Armando
AU - de Vries-Bouwstra, Jeska
AU - Wijmenga, Cisca
AU - Koeleman, Bobby P.C.
AU - Nordin, Annika
AU - Padyukov, Leonid
AU - Hoffmann-Vold, Anna Maria
AU - Lie, Benedicte
AU - Ríos, R.
AU - Callejas, J. L.
AU - Vargas-Hitos, J. A.
AU - García-Portales, R.
AU - Camps, M. T.
AU - Fernández-Nebro, A.
AU - González-Escribano, M. F.
AU - García-Hernández, F. J.
AU - Castillo, M. J.
AU - Aguirre, M. A.
AU - Gómez-Gracia, I.
AU - Fernández-Gutiérrez, B.
AU - Rodríguez-Rodríguez, L.
AU - García de la Peña, P.
AU - Vicente, E.
AU - Andreu, J. L.
AU - Fernández de Castro, M.
AU - López-Longo, F. J.
AU - Martínez, L.
AU - Fonollosa,
AU - Guillén, A.
AU - Riemekasten, G.
N1 - Funding Information:
We thank Sofia Vargas, Sonia García, and Gema Robledo for their excellent technical assistance and all the patients and control donors for their essential collaboration. We thank National DNA Bank Carlos III (University of Salamanca, Spain) that supplied part of the control DNA samples from Spain, WTCCC and EIRA Consortiums, and PopGen 2.0 network. This work was supported by Spanish Ministry of Economy and Competitiveness (grant ref. SAF2015-66761-P), Consejeria de Innovacion, Ciencia y Tecnologia, Junta de Andalucía (P12-BIO-1395), Ministerio de Educación, Cultura y Deporte through the program FPU, Juan de la Cierva fellowship (FJCI-2015-24028), Red de Investigación en Inflamación y Enfermadades Reumaticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013), and Scleroderma Research Foundation and NIH P50-HG007735 (to H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. PopGen 2.0 is supported by a grant from the German Ministry for Education and Research (01EY1103). M.D.M and S.A. are supported by grant DoD W81XWH-18-1-0423 and DoD W81XWH-16-1-0296, respectively.
Publisher Copyright:
© 2019, The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85074256049&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12760-y
DO - 10.1038/s41467-019-12760-y
M3 - Journal articles
C2 - 31672989
AN - SCOPUS:85074256049
SN - 1751-8628
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
ER -