Format

Send to

Choose Destination
Nat Commun. 2019 Oct 31;10(1):4955. doi: 10.1038/s41467-019-12760-y.

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

Author information

1
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain. eisac.csic@gmail.com.
2
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain.
3
The University of Texas Health Science Center-Houston, Houston, USA.
4
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
5
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
6
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy.
7
Department of Internal Medicine, Valle de Hebrón Hospital, Barcelona, Spain.
8
Department of Rheumatology, 12 de Octubre University Hospital, Madrid, Spain.
9
Department of Internal Medicine, San Cecilio Clinic University Hospital, Granada, Spain.
10
Department of Rheumatology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain.
11
Wellcome Trust Sanger Institute, Hinxton, UK.
12
Department of Genetics and Institute of Biotechnology, University of Granada, Granada, Spain.
13
Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Oxford Road, Manchester, UK.
14
Department of Dermatology, University of Cologne, Cologne, Germany.
15
Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
16
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
17
Department of Medicine, Università degli Studi di Verona, Verona, Italy.
18
Clinica Medica, Department of Clinical and Molecular Science, Università Politecnica delle Marche and Ospedali Riuniti, Ancona, Italy.
19
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
20
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
21
University Medical Center Utrecht, Utrecht, The Netherlands.
22
Division of Rheumatology, Department of Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
23
Department of Rheumatology, Oslo University Hospital, Oslo, Norway.
24
Department of Medical Genetics, and the Department of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway.
25
Royal Adelaide Hospital and University of Adelaide, Adelaide, SA, Australia.
26
St. Vincent's Hospital, Melbourne, VIC, Australia.
27
The University of Melbourne at St. Vincent's Hospital, Melbourne, VIC, Australia.
28
Department of Medical and Molecular Genetics, King's College London, London, UK.
29
Centre for Musculoskeletal Research, The University of Manchester, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
30
NIHR Manchester Biomedical Research Centre, Manchester, UK.
31
Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom.
32
Department of Rheumatology A, Cochin Hospital, INSERM U1016, Paris Descartes University, Paris, France.
33
Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, QLD, Australia.
34
Department of Rheumatology & Clinical Immunology, Laboratory of Translational Immunology, department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
35
Institute of Parasitology and Biomedicine López-Neyra, IPBLN-CSIC, Granada, Spain. javiermartin@ipb.csic.es.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center