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

Research output: Contribution to journalArticle


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. © 2019, The Author(s).


  • Elena López-Isac
  • Roger Hesselstrand
  • Javier Martin
  • European Scleroderma Group
  • Australian Scleroderma Interest Group (ASIG)
External organisations
  • CSIC Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN)
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Rheumatology and Autoimmunity
  • Medical Genetics


  • c terminal src kinase, centromere antibody, cluster of differentiation 247, complexin 3, diacylglycerol kinase theta, gasdermin A, histone 3 lysine 27, interferon consensus sequence binding protein, interleukin 12 receptor subunit beta 1, interleukin 12 receptor subunit beta 2, lectin, mannose binding 1 like, mitochondrial ribosomal protein s7, nucleoporin 85, ORMDL sphingolipid biosynthesis regulator 3, phosphopantothenoylcysteine decarboxylase, post GPI attachment to proteins 3, proteasome 26S subunit, non-ATPase 3, Rho GTPase activating protein 31, ribonuclease P and MRP subunit p25, STAT4 protein, TNFAIP3 interacting protein 1, transcription factor, unclassified drug, zona pellucida binding protein 2, cell, cell component, disease incidence, genetic analysis, genome, meta-analysis, mortality, Article, Bayesian network, CD4+ T lymphocyte, cell expansion, cohort analysis, controlled study, epigenetics, fibrosis, gene identification, gene locus, genome-wide association study, human, immune response, major clinical study, molecular genetics, protein acetylation, rheumatic disease, risk factor, single nucleotide polymorphism, systemic sclerosis, T lymphocyte, vascular disease
Original languageEnglish
Article number4955
JournalNature Communications
Issue number1
Publication statusPublished - 2019
Publication categoryResearch

Bibliographic note

Export Date: 15 November 2019