1. GWAS for systemic sclerosis identifies multiple risk loci and highlights fibrotic and vasculopathy pathways
- Author
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López-Isac, E., Acosta-Herrera, M., Kerick, M., Assassi, S., Satpathy, A.T., Granja, J., Mumbach, M.R., Beretta, L., Simeón, C.P., Carreira, P., Ortego-Centeno, N., Castellvi, I., Bossini-Castillo, L., Carmona, F.D., Orozco, G., Hunzelmann, N., Distler, J.H.W., Franke, A., Lunardi, C., Moroncini, G., Gabrielli, A., de Vries-Bouwstra, J., Wijmenga, C., Koeleman, B.P.C., Nordin, A., Padyukov, L., Hoffmann-Vold, A.-M., Lie, B., Ríos, R., Callejas, J.L., Vargas-Hitos, J.A., García-Portales, R., Camps, M.T., Fernández-Nebro, A., González-Escribano, M.F., García-Hernández, F.J., Castillo, M.J., Aguirre, M.A., Gómez-Gracia, I., Fernández-Gutiérrez, B., Rodríguez-Rodríguez, L., García de la Peña, P., Vicente, E., Andreu, J.L., Fernández de Castro, M., López-Longo, F.J., Martínez, L., Fonollosa, V., Guillén, A., Espinosa, G., Tolosa, C., Pros, A., Rodríguez-Carballeira, M., Narváez, F.J., Rubio-Rivas, M., Ortiz-Santamaría, V, Madroñero, A.B., González-Gay, M.A., Díaz, B., Trapiella, L., Sousa, A., Egurbide, M.V., Fanlo-Mateo, P., Sáez-Comet, L., Díaz, F., Hernández, V, Beltrán, E., Román-Ivorra, J.A., Grau E., Alegre-Sancho, J.J., Freire, M., Blanco-García, F.J., Oreiro, N., Witte, T., Kreuter, A., Riemekasten, G., Airó P., Magro, C., Voskuyl, A.E., Vonk, M.C., 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, A.L., Worthington, J., Denton C.P., Allanore, Y., Brown, M.A., Radstake, T.R.D.J., Fonseca, C., Chang H.Y., Mayes, M.D., Martin, J., European Scleroderma Group, Australian Scleroderma Interest Group (ASIG), Universidad de Salamanca, Ministerio de Economía y Competitividad (España), Junta de Andalucía, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Howard Hughes Medical Institute, Federal Ministry of Education and Research (Germany), Universidad de Cantabria, [López-Isac E, Acosta-Herrera M, Kerick M] Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain. [Assassi S] The University of Texas Health Science Center-Houston, Houston, USA. [Satpathy AT, Granja J] Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, USA. Howard Hughes Medical Institute, Stanford University, Stanford, USA. [Simeón CP] Servei de Medicina Interna, Vall d'Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Rheumatology, and AII - Inflammatory diseases
- Subjects
0301 basic medicine ,Chemistry(all) ,AUTOIMMUNITY ,Àcids nucleics ,General Physics and Astronomy ,Genome-wide association study ,Disease ,VARIANTS ,Biochemistry ,ANNOTATION ,0302 clinical medicine ,Phosphopantothenoylcysteine decarboxylase ,Single nucleotide ,Non-U.S. Gov't ,lcsh:Science ,skin and connective tissue diseases ,características del estudio::metaanálisis [CARACTERÍSTICAS DE PUBLICACIONES] ,Multidisciplinary ,Nucleid acid conformation ,integumentary system ,Research Support, Non-U.S. Gov't ,High-Throughput Nucleotide Sequencing ,Genètica - Tècnica ,3. Good health ,Nucleic acids ,Sequence analysis DNA ,Medical genetics ,medicine.medical_specialty ,Chromatin Immunoprecipitation ,GENES ,Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Science ,Non-P.H.S ,Single-nucleotide polymorphism ,Scleroderma systemic ,Computational biology ,Physics and Astronomy(all) ,Biology ,Research Support ,Study Characteristics::Meta-Analysis [PUBLICATION CHARACTERISTICS] ,Genetic polymorphisms ,enfermedades de la piel y tejido conjuntivo::enfermedades del tejido conjuntivo::esclerodermia sistémica [ENFERMEDADES] ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Functional genomics, Genome-wide association studies, Systemic sclerosis, Rheumatic diseases ,CLASSIFICATION ,N.I.H ,03 medical and health sciences ,Research Support, N.I.H., Extramural ,Diacylglycerol kinase theta ,Molecular genetics ,REVEALS ,Journal Article ,medicine ,Humans ,Vascular Diseases ,Risk factor ,Polymorphism ,Genomes ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,030203 arthritis & rheumatology ,Scleroderma, Systemic ,Biochemistry, Genetics and Molecular Biology(all) ,Polimorfisme genètic ,HUMAN-CELLS ,Extramural ,Bayes Theorem ,General Chemistry ,Sequence Analysis, DNA ,Fibrosis ,030104 developmental biology ,Scleroderma (Disease) ,Skin and Connective Tissue Diseases::Connective Tissue Diseases::Scleroderma, Systemic [DISEASES] ,técnicas de investigación::métodos epidemiológicos::diseño de la investigación epidemiológica::estudio de asociación genómica completa [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Nucleic Acid Conformation ,VISUALIZATION ,lcsh:Q ,U.S. Gov't ,Esclerodèrmia ,Research Support, U.S. Gov't, Non-P.H.S ,Metaanàlisi ,Genetics and Molecular Biology(all) ,Genome-Wide Association Study - 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., 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
- Published
- 2019