GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
Por:
Lopez-Isac, E, Acosta-Herrera, M, Kerick, M, Assassi, S, Satpathy, AT, Granja, J, Mumbach, MR, Beretta, L, Simeon, CP, Carreira, P, Ortego-Centeno, N, Castellvi, I, Bossini-Castillo, L, Carmona, FD, Orozco, G, Hunzelmann, N, Distler, JHW, Franke, A, Lunardi, C, Moroncini, G, Gabrielli, A, de Vries-Bouwstra, J, Wijmenga, C, Koeleman, BPC, Nordin, A, Padyukov, L, Hoffmann-Vold, AM, Lie, B, Rios, R, Callejas, JL, Vargas-Hitos, JA, Garcia-Portales, R, Camps, MT, Fernandez-Nebro, A, Gonzalez-Escribano, MF, Garcia-Hernandez, FJ, Castillo, MJ, Aguirre, MA, Gomez-Gracia, I, Fernandez-Gutierrez, B, Rodriguez-Rodriguez, L, de la Pena, PG, Vicente, E, Andreu, JL, de Castro, MF, Lopez-Longo, FJ, Martinez, L, Fonollosa, V, Guillen, A, Espinosa, G, Tolosa, C, Pros, A, Rodriguez-Carballeira, M, Narvaez, FJ, Rubio-Rivas, M, Ortiz-Santamaria, V, Madronero, AB, Gonzalez-Gay, MA, Diaz, B, Trapiella, L, Sousa, A, Egurbide, MV, Fanlo-Mateo, P, Saez-Comet, L, Diaz, F, Hernandez, V, Beltran, E, Roman-Ivorra, JA, Grau, E, Alegre-Sancho, JJ, Freire, M, Blanco-Garcia, FJ, Oreiro, N, Witte, T, Kreuter, A, Riemekasten, G, Airo, 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, TRDJ, Fonseca, C, Chang, HY, Mayes, MD, Martin, J, European Scleroderma Grp, ASIG
Publicada:
31 oct 2019
Resumen:
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.
Filiaciones:
Lopez-Isac, E:
CSIC, IPBLN, Granada, Spain
Acosta-Herrera, M:
CSIC, IPBLN, Granada, Spain
Kerick, M:
CSIC, IPBLN, Granada, Spain
Assassi, S:
Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA
Satpathy, AT:
Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA
Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
Granja, J:
Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA
Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
Mumbach, MR:
Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA
Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
Beretta, L:
Fdn IRCCS Ca Granda Osped Maggiore Policlin Milan, Referral Ctr System Autoimmune Dis, Milan, Italy
Simeon, CP:
Valle Hebron Hosp, Dept Internal Med, Barcelona, Spain
Carreira, P:
12 Octubre Univ Hosp, Dept Rheumatol, Madrid, Spain
Ortego-Centeno, N:
San Cecilio Clin Univ Hosp, Dept Internal Med, Granada, Spain
Castellvi, I:
Santa Creu & St Pau Univ Hosp, Dept Rheumatol, Barcelona, Spain
Bossini-Castillo, L:
Wellcome Trust Sanger Inst, Hinxton, England
Carmona, FD:
Univ Granada, Dept Genet, Granada, Spain
Univ Granada, Inst Biotechnol, Granada, Spain
Orozco, G:
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
Hunzelmann, N:
Univ Cologne, Dept Dermatol, Cologne, Germany
Distler, JHW:
Univ Erlangen Nurnberg, Inst Clin Immunol, Dept Internal Med 3, Erlangen, Germany
Franke, A:
Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
Lunardi, C:
Univ Verona, Dept Med, Verona, Italy
Moroncini, G:
Univ Politecn Marche, Dept Clin & Mol Sci, Clin Med, Ancona, Italy
Osped Riuniti, Ancona, Italy
Gabrielli, A:
Univ Politecn Marche, Dept Clin & Mol Sci, Clin Med, Ancona, Italy
Osped Riuniti, Ancona, Italy
de Vries-Bouwstra, J:
Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands
Wijmenga, C:
Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands
Koeleman, BPC:
Univ Med Ctr Utrecht, Utrecht, Netherlands
Nordin, A:
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Rheumatol, Stockholm, Sweden
Padyukov, L:
Karolinska Univ Hosp, Karolinska Inst, Dept Med, Div Rheumatol, Stockholm, Sweden
Hoffmann-Vold, AM:
Oslo Univ Hosp, Dept Rheumatol, Oslo, Norway
Lie, B:
Univ Oslo, Dept Med Genet, Oslo, Norway
Univ Oslo, Dept Immunol, Oslo, Norway
Oslo Univ Hosp, Oslo, Norway
Rios, R:
San Cecilio Clin Univ Hosp, Dept Internal Med, Granada, Spain
Callejas, JL:
San Cecilio Clin Univ Hosp, Dept Internal Med, Granada, Spain
Vargas-Hitos, JA:
Virgen Las Nieves Hosp, Dept Internal Med, Granada, Spain
Garcia-Portales, R:
Virgen Victoria Hosp, Dept Rheumatol, Malaga, Spain
Camps, MT:
Carlos Haya Hosp, Dept Internal Med, Malaga, Spain
Fernandez-Nebro, A:
Carlos Haya Hosp, Dept Rheumatol, Malaga, Spain
Gonzalez-Escribano, MF:
Virgen Rocio Hosp, Dept Immunol, Seville, Spain
Garcia-Hernandez, FJ:
Virgen Rocio Hosp, Dept Internal Med, Seville, Spain
Castillo, MJ:
Virgen Rocio Hosp, Dept Internal Med, Seville, Spain
Aguirre, MA:
Reina Sofia IMIBIC Hosp, Dept Rheumatol, Cordoba, Spain
Gomez-Gracia, I:
Reina Sofia IMIBIC Hosp, Dept Rheumatol, Cordoba, Spain
Fernandez-Gutierrez, B:
San Carlos Clin Hosp, Dept Rheumatol, Madrid, Spain
Rodriguez-Rodriguez, L:
San Carlos Clin Hosp, Dept Rheumatol, Madrid, Spain
de la Pena, PG:
Madrid Norte Sanchinarro Hosp, Dept Rheumatol, Madrid, Spain
Vicente, E:
La Princesa Hosp, Dept Rheumatol, Madrid, Spain
Andreu, JL:
Puerta Hierro Hosp Majadahonda, Dept Rheumatol, Madrid, Spain
de Castro, MF:
Puerta Hierro Hosp Majadahonda, Dept Rheumatol, Madrid, Spain
Lopez-Longo, FJ:
Gregorio Maranon Univ Hosp, Dept Rheumatol, Madrid, Spain
Martinez, L:
Gregorio Maranon Univ Hosp, Dept Rheumatol, Madrid, Spain
Fonollosa, V:
Valle Hebron Hosp, Dept Internal Med, Barcelona, Spain
Guillen, A:
Valle Hebron Hosp, Dept Internal Med, Barcelona, Spain
Espinosa, G:
Clin Hosp, Dept Internal Med, Barcelona, Spain
Tolosa, C:
Parc Tauli Hosp, Dept Internal Med, Sabadell, Spain
Pros, A:
Hosp del Mar, Dept Rheumatol, Barcelona, Spain
Rodriguez-Carballeira, M:
Hosp Univ Mutua Terrasa, Dept Internal Med, Barcelona, Spain
Narvaez, FJ:
Bellvitge Univ Hosp, Dept Rheumatol, Barcelona, Spain
Rubio-Rivas, M:
Bellvitge Univ Hosp, Dept Internal Med, Barcelona, Spain
Ortiz-Santamaria, V:
Granollers Hosp, Dept Rheumatol, Granollers, Spain
Madronero, AB:
Hosp Gen San Jorge, Dept Internal Med, Huesca, Spain
Gonzalez-Gay, MA:
Univ Cantabria, Epidemiol Genet & Atherosclerosis Res Grp Syst In, DIVAL, Santander, Spain
Diaz, B:
Hosp Cent Asturias, Dept Internal Med, Oviedo, Spain
Trapiella, L:
Hosp Cent Asturias, Dept Internal Med, Oviedo, Spain
Sousa, A:
Complexo Hosp Univ Vigo, Hosp Xeral, Dept Internal Med, Infect Dis Unit, Vigo, Spain
Egurbide, MV:
Hosp Univ Cruces, Dept Internal Med, Baracaldo, Spain
Fanlo-Mateo, P:
Hosp Virgen Camino, Dept Internal Med, Pamplona, Spain
Saez-Comet, L:
Hosp Univ Miguel Servet, Dept Internal Med, Zaragoza, Spain
Diaz, F:
Hosp Univ Canarias, Dept Rheumatol, Tenerife, Spain
Hernandez, V:
Hosp Univ Canarias, Dept Rheumatol, Tenerife, Spain
Beltran, E:
Hosp Gen Univ Valencia, Dept Rheumatol, Valencia, Spain
Roman-Ivorra, JA:
Hosp Univ & Politecn La Fe, Dept Rheumatol, Valencia, Spain
Grau, E:
Hosp Univ & Politecn La Fe, Dept Rheumatol, Valencia, Spain
Alegre-Sancho, JJ:
Hosp Univ Doctor Peset, Dept Rheumatol, Valencia, Spain
Freire, M:
Complexo Hosp Univ Vigo, Dept Internal Med, Thrombosis & Vasculitis Unit, Vigo, Spain
Blanco-Garcia, FJ:
INIBIC Hosp Univ A Coruna, Dept Rheumatol, La Coruna, Spain
Oreiro, N:
INIBIC Hosp Univ A Coruna, Dept Rheumatol, La Coruna, Spain
Witte, T:
Hannover Med Sch, Dept Clin Immunol, Hannover, Germany
Kreuter, A:
Ruhr Univ Bochum, Josefs Hosp, Dept Dermatol, Bochum, Germany
Riemekasten, G:
Univ Lubeck, Clin Rheumatol, Lubeck, Germany
Airo, P:
Spedali Civil Brescia, Serv Rheumatol & Clin Immunol, Brescia, Italy
Magro, C:
Leiden Univ, Dept Rheumatol, Med Ctr, Leiden, Netherlands
Voskuyl, AE:
Vrije Univ Amsterdam, Med Ctr, Dept Rheumatol, Amsterdam, Netherlands
Hesselstrand, R:
Lund Univ, Dept Rheumatol, Lund, Sweden
Proudman, S:
Royal Adelaide Hosp, Adelaide, SA, Australia
Univ Adelaide, Adelaide, SA, Australia
Stevens, W:
St Vincents Hosp, Melbourne, Vic, Australia
Nikpour, M:
Univ Melbourne, St Vincents Hosp, Melbourne, Vic, Australia
Zochling, J:
Univ Tasmania, Menzies Res Inst Tasmania, Hobart, Tas, Australia
Sahhar, J:
Monash Med Ctr, Dept Rheumatol, Melbourne, Vic, Australia
Roddy, J:
Royal Perth Hosp, Rheumatol, Perth, WA, Australia
Nash, P:
Sunshine Coast Rheumatol, Res Unit, Maroochydore, Qld, Australia
Tymms, K:
Canberra Rheumatol, Canberra, ACT, Australia
Rischmueller, M:
Queen Elizabeth Hosp, Dept Rheumatol, Woodville, SA, Australia
Lester, S:
Queen Elizabeth Hosp, Dept Rheumatol, Woodville, SA, Australia
Vyse, T:
Kings Coll London, Dept Med & Mol Genet, London, England
Herrick, AL:
Univ Manchester, Manchester Acad Hlth Sci Ctr, Salford Royal NHS Fdn Trust, Ctr Musculoskeletal Res, Manchester, Lancs, England
NIHR Manchester Biomed Res Ctr, Manchester, Lancs, England
Worthington, J:
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
Denton, CP:
Royal Free & Univ Coll Med Sch, Ctr Rheumatol, London, England
Allanore, Y:
Paris Descartes Univ, Cochin Hosp, Dept Rheumatol A, INSERM,U1016, Paris, France
Brown, MA:
Queensland Univ Technol, Translat Res Inst, Princess Alexandra Hosp, Inst Hlth & Biomed Innovat, Brisbane, Qld, Australia
Radstake, TRDJ:
Univ Med Ctr Utrecht, Dept Immunol, Dept Rheumatol Clin Immunol, Lab Translat Immunol, Utrecht, Netherlands
Fonseca, C:
Royal Free & Univ Coll Med Sch, Ctr Rheumatol, London, England
Chang, HY:
Stanford Univ, Sch Med, Ctr Personal Dynam Regulomes, Stanford, CA 94305 USA
Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
Mayes, MD:
Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA
Martin, J:
CSIC, IPBLN, Granada, Spain
Radboud Univ Nijmegen, Med Ctr, Dept Rheumatol, Nijmegen, Netherlands.
Gold, Green Published
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