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- Title
Integrated genomic and prospective clinical studies show the importance of modular pleiotropy for disease susceptibility, diagnosis and treatment.
- Authors
Gustafsson, Mika; Edström, Måns; Danuta Gawel; Nestor, Colm E.; Hui Wang; Huan Zhang; Barrenäs, Fredrik; Tojo, James; Kockum, Ingrid; Olsson, Tomas; Serra-Musach, Jordi; Bonifaci, Núria; Pujana, Miguel Angel; Ernerudh, Jan; Benson, Mikael
- Abstract
Background Translational research typically aims to identify and functionally validate individual, diseasespecific 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, i.e. 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 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.
- Subjects
GENETIC pleiotropy; MEDICAL genomics; META-analysis; CD4 antigen; GENE ontology; FISHER exact test
- Publication
Genome Medicine, 2014, Vol 6, Issue 2, p1
- ISSN
1756-994X
- Publication type
Article
- DOI
10.1186/gm534