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Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Clinical and Experimental Medicine, Faculty of Health Sciences, Division of Clinical Immunology, Unit of Autoimmunity and Immune Regulation, Linköping University, Linköping, Sweden.ORCID iD: 0000-0002-5558-1864
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
The Centre for Individualised Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
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2014 (English)In: Genome Medicine, E-ISSN 1756-994X, Vol. 6, no 2, article id 17Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BioMed Central, 2014. Vol. 6, no 2, article id 17
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:oru:diva-97549DOI: 10.1186/gm534ISI: 000334631300002PubMedID: 24571673Scopus ID: 2-s2.0-84899648957OAI: oai:DiVA.org:oru-97549DiVA, id: diva2:1638197
Funder
European Commission, 223367AFA InsuranceKnut and Alice Wallenberg FoundationThe Swedish Brain FoundationSwedish Research Council
Note

Funding agency:

Instituto de Salud Carlos III Spanish Government   ISCIII FIS 12/01528, RTICC RD12/0036/0008 

Available from: 2022-02-16 Created: 2022-02-16 Last updated: 2024-07-04Bibliographically approved

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