title: Integrated genomics identifies convergence of ankylosing spondylitis with global immune mediated disease pathways.
abstract: 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.
authors.affiliation: Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Uddin
authors.affiliation: Faculty of Medicine, Memorial University, Newfoundland, St. John's, Canada.
authors.forename: Dianne
authors.initials: D
authors.lastname: Codner
authors.affiliation: Faculty of Medicine, Memorial University, Newfoundland, St. John's, Canada.
authors.forename: S M Mahmud
authors.initials: SM
authors.lastname: Hasan
authors.affiliation: 1] Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada [2] McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada [3] Department of Molecular Genetics, University of Toronto, Ontario, Canada.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Faculty of Medicine, Memorial University, Newfoundland, St. John's, Canada.
authors.forename: Darren D
authors.initials: DD
authors.lastname: O'Rielly
authors.affiliation: Faculty of Medicine, Memorial University, Newfoundland, St. John's, Canada.
authors.forename: Proton
authors.initials: P
authors.lastname: Rahman
mesh_terms: D004198:Disease Susceptibility; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D007109:Immunity; D009154:Mutation; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D050795:STAT2 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013167:Spondylitis, Ankylosing / Q000209:etiology*; D014158:Transcription, Genetic
chemical_list: D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor