title: Targeted genomic analysis reveals widespread autoimmune disease association with regulatory variants in the TNF superfamily cytokine signalling network.
abstract: Tumour necrosis factor (TNF) superfamily cytokines and their receptors regulate diverse immune system functions through a common set of signalling pathways. Genetic variants in and expression of individual TNF superfamily cytokines, receptors and signalling proteins have been associated with autoimmune and inflammatory diseases, but their interconnected biology has been largely unexplored.
  
  
  
  We took a hypothesis-driven approach using available genome-wide datasets to identify genetic variants regulating gene expression in the TNF superfamily cytokine signalling network and the association of these variants with autoimmune and autoinflammatory disease. Using paired gene expression and genetic data, we identified genetic variants associated with gene expression, expression quantitative trait loci (eQTLs), in four peripheral blood cell subsets. We then examined whether eQTLs were dependent on gene expression level or the presence of active enhancer chromatin marks. Using these eQTLs as genetic markers of the TNF superfamily signalling network, we performed targeted gene set association analysis in eight autoimmune and autoinflammatory disease genome-wide association studies.
  
  
  
  Comparison of TNF superfamily network gene expression and regulatory variants across four leucocyte subsets revealed patterns that differed between cell types. eQTLs for genes in this network were not dependent on absolute gene expression levels and were not enriched for chromatin marks of active enhancers. By examining autoimmune disease risk variants among our eQTLs, we found that risk alleles can be associated with either increased or decreased expression of co-stimulatory TNF superfamily cytokines, receptors or downstream signalling molecules. Gene set disease association analysis revealed that eQTLs for genes in the TNF superfamily pathway were associated with six of the eight autoimmune and autoinflammatory diseases examined, demonstrating associations beyond single genome-wide significant hits.
  
  
  
  This systematic analysis of the influence of regulatory genetic variants in the TNF superfamily network reveals widespread and diverse roles for these cytokines in susceptibility to a number of immune-mediated diseases.
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.|Autoimmunity Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Arianne C
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: Peters
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: James C
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Genetics, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Golnaz
authors.initials: G
authors.lastname: Vahedi
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD, 20894, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Autoimmunity Branch, National Institute for Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.affiliation: Department of Medicine and Cambridge Institute for Medical Research, The University of Cambridge, Box 139, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK. kgcs2@cam.ac.uk.
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
mesh_terms: D000483:Alleles; D001327:Autoimmune Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000276:immunology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D056660:Hereditary Autoinflammatory Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D040641:Quantitative Trait Loci; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000276:immunology; D012306:Risk; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
chemical_list: D002843:Chromatin; D020033:Protein Isoforms; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha
keywords: Autoimmunity; Autoinflammation; GWAS; Gene set analysis; Genetics; Genomics; TNF superfamily; eQTL