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

被引：126

作者：

Lopez-Isac, Elena ^{[1
]}

Acosta-Herrera, Marialbert ^{[1
]}

Kerick, Martin ^{[1
]}

Assassi, Shervin ^{[2
]}

Satpathy, Ansuman T. ^{[3
,4
]}

Granja, Jeffrey ^{[3
,4
]}

Mumbach, Maxwell R. ^{[3
,4
]}

Beretta, Lorenzo ^{[5
]}

Simeon, Carmen P. ^{[6
]}

Carreira, Patricia ^{[7
]}

Ortego-Centeno, Norberto ^{[8
]}

Castellvi, Ivan ^{[9
]}

Bossini-Castillo, Lara ^{[10
]}

David Carmona, F. ^{[11
,12
]}

Orozco, Gisela ^{[13
]}

Hunzelmann, Nicolas ^{[14
]}

Distler, Joerg H. W. ^{[15
]}

Franke, Andre ^{[16
]}

Lunardi, Claudio ^{[17
]}

Moroncini, Gianluca ^{[18
,19
]}

Gabrielli, Armando ^{[18
,19
]}

de Vries-Bouwstra, Jeska ^{[20
]}

Wijmenga, Cisca ^{[21
]}

Koeleman, Bobby P. C. ^{[22
]}

Nordin, Annika ^{[23
]}

Padyukov, Leonid ^{[23
]}

Hoffmann-Vold, Anna-Maria ^{[24
]}

Lie, Benedicte ^{[25
,26
,27
]}

Rios, R. ^{[8
]}

Callejas, J. L. ^{[8
]}

Vargas-Hitos, J. A. ^{[39
]}

Garcia-Portales, R. ^{[40
]}

Camps, M. T. ^{[41
]}

Fernandez-Nebro, A. ^{[42
]}

Gonzalez-Escribano, M. F. ^{[43
]}

Garcia-Hernandez, F. J. ^{[44
]}

Castillo, M. J. ^{[44
]}

Aguirre, M. A. ^{[45
]}

Gomez-Gracia, I. ^{[45
]}

Fernandez-Gutierrez, B. ^{[46
]}

Rodriguez-Rodriguez, L. ^{[46
]}

Garcia de la Pena, P. ^{[47
]}

Vicente, E. ^{[48
]}

Andreu, J. L. ^{[49
]}

Fernandez de Castro, M. ^{[49
]}

Lopez-Longo, F. J. ^{[50
]}

Martinez, L. ^{[50
]}

Fonollosa, V ^{[6
]}

Guillen, A. ^{[6
]}

Espinosa, G. ^{[51
]}

机构：

[1] CSIC, IPBLN, Granada, Spain

[2] Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA

[3] Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA

[4] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA

[5] Fdn IRCCS Ca Granda Osped Maggiore Policlin Milan, Referral Ctr System Autoimmune Dis, Milan, Italy

[6] Valle Hebron Hosp, Dept Internal Med, Barcelona, Spain

[7] 12 Octubre Univ Hosp, Dept Rheumatol, Madrid, Spain

[8] San Cecilio Clin Univ Hosp, Dept Internal Med, Granada, Spain

[9] Santa Creu & St Pau Univ Hosp, Dept Rheumatol, Barcelona, Spain

[10] Wellcome Trust Sanger Inst, Hinxton, England

[11] Univ Granada, Dept Genet, Granada, Spain

[12] Univ Granada, Inst Biotechnol, Granada, Spain

[13] Univ Manchester, Manchester Acad Hlth Sci Ctr, Arthrit Res UK Ctr Genet & Genom, Ctr Musculoskeletal Res,Fac Biol Med & Hlth, Oxford Rd, Manchester, Lancs, England

[14] Univ Cologne, Dept Dermatol, Cologne, Germany

[15] Univ Erlangen Nurnberg, Inst Clin Immunol, Dept Internal Med 3, Erlangen, Germany

[16] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[17] Univ Verona, Dept Med, Verona, Italy

[18] Univ Politecn Marche, Dept Clin & Mol Sci, Clin Med, Ancona, Italy

[19] Osped Riuniti, Ancona, Italy

[20] Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands

[21] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[22] Univ Med Ctr Utrecht, Utrecht, Netherlands

[23] Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Rheumatol, Stockholm, Sweden

[24] Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway

[25] Univ Oslo, Dept Med Genet, Oslo, Norway

[26] Univ Oslo, Dept Immunol, Oslo, Norway

[27] Oslo Univ Hosp, Oslo, Norway

[28] Royal Adelaide Hosp, Adelaide, SA, Australia

[29] Univ Adelaide, Adelaide, SA, Australia

[30] St Vincents Hosp, Melbourne, Vic, Australia

[31] Univ Melbourne, St Vincents Hosp, Melbourne, Vic, Australia

[32] Kings Coll London, Dept Med & Mol Genet, London, England

[33] Univ Manchester, Manchester Acad Hlth Sci Ctr, Salford Royal NHS Fdn Trust, Ctr Musculoskeletal Res, Manchester, Lancs, England

[34] NIHR Manchester Biomed Res Ctr, Manchester, Lancs, England

[35] Royal Free & Univ Coll Med Sch, Ctr Rheumatol, London, England

[36] Paris Descartes Univ, Cochin Hosp, Dept Rheumatol A, INSERM,U1016, Paris, France

[37] Queensland Univ Technol, Translat Res Inst, Princess Alexandra Hosp, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia

[38] Univ Med Ctr Utrecht, Dept Immunol, Dept Rheumatol Clin Immunol, Lab Translat Immunol, Utrecht, Netherlands

[39] Virgen Las Nieves Hosp, Dept Internal Med, Granada, Spain

[40] Virgen Victoria Hosp, Dept Rheumatol, Malaga, Spain

[41] Carlos Haya Hosp, Dept Internal Med, Malaga, Spain

[42] Carlos Haya Hosp, Dept Rheumatol, Malaga, Spain

[43] Virgen Rocio Hosp, Dept Immunol, Seville, Spain

[44] Virgen Rocio Hosp, Dept Internal Med, Seville, Spain

[45] Reina Sofia IMIBIC Hosp, Dept Rheumatol, Cordoba, Spain

[46] San Carlos Clin Hosp, Dept Rheumatol, Madrid, Spain

[47] Madrid Norte Sanchinarro Hosp, Dept Rheumatol, Madrid, Spain

[48] La Princesa Hosp, Dept Rheumatol, Madrid, Spain

[49] Puerta Hierro Hosp Majadahonda, Dept Rheumatol, Madrid, Spain

[50] Gregorio Maranon Univ Hosp, Dept Rheumatol, Madrid, Spain

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

GENOME-WIDE ASSOCIATION; HUMAN-CELLS; VARIANTS; REVEALS; ANNOTATION; GENES; CLASSIFICATION; VISUALIZATION; AUTOIMMUNITY; METAANALYSIS;

D O I：

10.1038/s41467-019-12760-y

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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