title: Integrative pathway analysis of genome-wide association studies and gene expression data in prostate cancer.
abstract: BACKGROUND
  Pathway analysis of large-scale omics data assists us with the examination of the cumulative effects of multiple functionally related genes, which are difficult to detect using the traditional single gene/marker analysis. So far, most of the genomic studies have been conducted in a single domain, e.g., by genome-wide association studies (GWAS) or microarray gene expression investigation. A combined analysis of disease susceptibility genes across multiple platforms at the pathway level is an urgent need because it can reveal more reliable and more biologically important information.
  
  
  RESULTS
  We performed an integrative pathway analysis of a GWAS dataset and a microarray gene expression dataset in prostate cancer. We obtained a comprehensive pathway annotation set from knowledge-based public resources, including KEGG pathways and the prostate cancer candidate gene set, and gene sets specifically defined based on cross-platform information. By leveraging on this pathway collection, we first searched for significant pathways in the GWAS dataset using four methods, which represent two broad groups of pathway analysis approaches. The significant pathways identified by each method varied greatly, but the results were more consistent within each method group than between groups. Next, we conducted a gene set enrichment analysis of the microarray gene expression data and found 13 pathways with cross-platform evidence, including "Fc gamma R-mediated phagocytosis" (P GWAS = 0.003, P expr < 0.001, and P combined = 6.18 × 10(-8)), "regulation of actin cytoskeleton" (P GWAS = 0.003, P expr = 0.009, and P combined = 3.34 × 10(-4)), and "Jak-STAT signaling pathway" (P GWAS = 0.001, P expr = 0.084, and P combined = 8.79 × 10(-4)).
  
  
  CONCLUSIONS
  Our results provide evidence at both the genetic variation and expression levels that several key pathways might have been involved in the pathological development of prostate cancer. Our framework that employs gene expression data to facilitate pathway analysis of GWAS data is not only feasible but also much needed in studying complex disease.
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008962:Models, Theoretical; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012641:Selection, Genetic; D015398:Signal Transduction