title: Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment.
abstract: BACKGROUND
  Translational research typically aims to identify and functionally validate individual, disease-specific genes. However, reaching this aim is complicated by the involvement of thousands of genes in common diseases, and that many of those genes are pleiotropic, that is, shared by several diseases.
  
  
  METHODS
  We integrated genomic meta-analyses with prospective clinical studies to systematically investigate the pathogenic, diagnostic and therapeutic roles of pleiotropic genes. In a novel approach, we first used pathway analysis of all published genome-wide association studies (GWAS) to find a cell type common to many diseases.
  
  
  RESULTS
  The analysis showed over-representation of the T helper cell differentiation pathway, which is expressed in T cells. This led us to focus on expression profiling of CD4(+) T cells from highly diverse inflammatory and malignant diseases. We found that pleiotropic genes were highly interconnected and formed a pleiotropic module, which was enriched for inflammatory, metabolic and proliferative pathways. The general relevance of this module was supported by highly significant enrichment of genetic variants identified by all GWAS and cancer studies, as well as known diagnostic and therapeutic targets. Prospective clinical studies of multiple sclerosis and allergy showed the importance of both pleiotropic and disease specific modules for clinical stratification.
  
  
  CONCLUSIONS
  In summary, this translational genomics study identified a pleiotropic module, which has key pathogenic, diagnostic and therapeutic roles.
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
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authors.affiliation: Clinical and Experimental Medicine, Faculty of Health Sciences, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, 58185 Linköping, Sweden.
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authors.lastname: Edström
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Danuta
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authors.lastname: Gawel
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Colm E
authors.initials: CE
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authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
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authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Huan
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authors.lastname: Zhang
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Fredrik
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authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet and Centrum for Molecular Medicine, 17177 Stockholm, Sweden.
authors.forename: James
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authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet and Centrum for Molecular Medicine, 17177 Stockholm, Sweden.
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authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet and Centrum for Molecular Medicine, 17177 Stockholm, Sweden.
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authors.affiliation: Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
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authors.affiliation: Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
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authors.lastname: Bonifaci
authors.affiliation: Cancer and Systems Biology Unit, Catalan Institute of Oncology, IDIBELL, L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
authors.forename: Miguel Angel
authors.initials: MA
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authors.affiliation: Clinical and Experimental Medicine, Faculty of Health Sciences, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, 58185 Linköping, Sweden.
authors.forename: Jan
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authors.lastname: Ernerudh
authors.affiliation: The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Mikael
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