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

European Scleroderma Group†; Australian Scleroderma Interest Group (ASIG)

doi:10.1038/s41467-019-12760-y

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

European Scleroderma Group†
, Australian Scleroderma Interest Group (ASIG)

Klinik für Rheumatologie und klinische Immunologie

Institute of Parasitology and Biomedicine López-Neyra
Baylor College of Medicine
Stanford University
IRCCS Fondazione Ca'Granda – Ospedale Maggiore Policlinico - Milano
Universitari Vall d'Hebrón
Hospital 12 de Octubre
Hospital Universitario San Cecilio
Hospital de La Santa Creu I Sant Pau
Wellcome Sanger Institute
University of Granada
University of Manchester
Universität zu Köln
Friedrich-Alexander-Universität Erlangen-Nürnberg
Christian-Albrechts Universität zu Kiel
University of Verona
Università Politecnica delle Marche
Leiden University
Universiteit Groningen
Utrecht University
Karolinska Institutet
University of Oslo
Hospital Universitario Virgen de las Nieves
Hospital Universitari Virgen de la Victoria
Hospital Regional Universitario Carlos Haya
Hospital Universitario Virgen del Rocio
Hospital Universitario Reina Sofia
Universidad Autónoma de Madrid (CSIC-UAM)
University Hospital Puerta de Hierro
General University Hospital

158 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	IET Communications
Jahrgang	10
Ausgabenummer	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-019-12760-y
Publikationsstatus	Veröffentlicht - 01.12.2019

Fördermittel

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.

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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10.1038/s41467-019-12760-y

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@article{227248932f7841ac87d8219f95ae8bce,

title = "GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways",

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.",

author = "\{European Scleroderma Group†\} and \{Australian Scleroderma Interest Group (ASIG)\} and Elena L{\'o}pez-Isac and Marialbert Acosta-Herrera and Martin Kerick and Shervin Assassi and Satpathy, \{Ansuman T.\} and Jeffrey Granja and Mumbach, \{Maxwell R.\} and Lorenzo Beretta and Sime{\'o}n, \{Carmen P.\} and Patricia Carreira and Norberto Ortego-Centeno and Ivan Castellvi and Lara Bossini-Castillo and Carmona, \{F. David\} and Gisela Orozco and Nicolas Hunzelmann and Distler, \{J{\"o}rg H.W.\} and Andre Franke and Claudio Lunardi and Gianluca Moroncini and Armando Gabrielli and \{de Vries-Bouwstra\}, Jeska and Cisca Wijmenga and Koeleman, \{Bobby P.C.\} and Annika Nordin and Leonid Padyukov and Hoffmann-Vold, \{Anna Maria\} and Benedicte Lie and R. R{\'i}os and Callejas, \{J. L.\} and Vargas-Hitos, \{J. A.\} and R. Garc{\'i}a-Portales and Camps, \{M. T.\} and A. Fern{\'a}ndez-Nebro and Gonz{\'a}lez-Escribano, \{M. F.\} and Garc{\'i}a-Hern{\'a}ndez, \{F. J.\} and Castillo, \{M. J.\} and Aguirre, \{M. A.\} and I. G{\'o}mez-Gracia and B. Fern{\'a}ndez-Guti{\'e}rrez and L. Rodr{\'i}guez-Rodr{\'i}guez and \{Garc{\'i}a de la Pe{\~n}a\}, P. and E. Vicente and Andreu, \{J. L.\} and \{Fern{\'a}ndez de Castro\}, M. and L{\'o}pez-Longo, \{F. J.\} and L. Mart{\'i}nez and Fonollosa and A. Guill{\'e}n and G. Riemekasten",

note = "Funding Information: We thank Sofia Vargas, Sonia Garc{\'i}a, 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 Andaluc{\'i}a (P12-BIO-1395), Ministerio de Educaci{\'o}n, Cultura y Deporte through the program FPU, Juan de la Cierva fellowship (FJCI-2015-24028), Red de Investigaci{\'o}n en Inflamaci{\'o}n 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: {\textcopyright} 2019, The Author(s). Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-12760-y",

language = "English",

volume = "10",

journal = "IET Communications",

issn = "1751-8628",

publisher = "John Wiley \& Sons Inc.",

number = "1",

}

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 - https://www.scopus.com/pages/publications/85074256049

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 - IET Communications

JF - IET Communications

IS - 1

ER -

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

Abstract

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UN SDGs

Strategische Forschungsbereiche und Zentren

Zugriff auf Dokument

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