Integrated genomics identifies convergence of ankylosing spondylitis with global immune mediated disease pathways

Sci Rep. 2015 May 18:5:10314. doi: 10.1038/srep10314.


Ankylosing spondylitis(AS), a highly heritable complex inflammatory arthritis. Although, a handful of non-HLA risk loci have been identified, capturing the unexplained genetic contribution to AS pathogenesis remains a challenge attributed to additive, pleiotropic and epistatic-interactions at the molecular level. Here, we developed multiple integrated genomic approaches to quantify molecular convergence of non-HLA loci with global immune mediated diseases. We show that non-HLA genes are significantly sensitive to deleterious mutation accumulation in the general population compared with tolerant genes. Human developmental proteomics (prenatal to adult) analysis revealed that proteins encoded by non-HLA AS risk loci are 2-fold more expressed in adult hematopoietic cells.Enrichment analysis revealed AS risk genes overlap with a significant number of immune related pathways (p < 0.0001 to 9.8 × 0(-12)). Protein-protein interaction analysis revealed non-shared AS risk genes are highly clustered seeds that significantly converge (empirical; p < 0.01 to 1.6 × 10(-4)) into networks of global immune mediated disease risk loci. We have also provided initial evidence for the involvement of STAT2/3 in AS pathogenesis. Collectively, these findings highlight molecular insight on non-HLA AS risk loci that are not exclusively connected with overlapping immune mediated diseases; rather a component of common pathophysiological pathways with other immune mediated diseases. This information will be pivotal to fully explain AS pathogenesis and identify new therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Disease Susceptibility
  • Gene Expression Regulation
  • Gene Regulatory Networks
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Genomics*
  • Humans
  • Immunity*
  • Mutation
  • Protein Interaction Mapping
  • Protein Interaction Maps
  • STAT2 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction*
  • Spondylitis, Ankylosing / etiology*
  • Transcription, Genetic


  • STAT2 Transcription Factor
  • STAT3 Transcription Factor