Multiplex meta-analysis of RNA expression to identify genes with variants associated with immune dysfunction

Abstract

Objective: We demonstrate a genome-wide method for the integration of many studies of gene expression of phenotypically similar disease processes, a method of multiplex meta-analysis. We use immune dysfunction as an example disease process. Design: We use a heterogeneous collection of datasets across human and mice samples from a range of tissues and different forms of immunodeficiency. We developed a method integrating Tibshirani's modified t-test (SAM) is used to interrogate differential expression within a study and Fisher's method for omnibus meta-analysis to identify differentially expressed genes across studies. The ability of this overall gene expression profile to prioritize disease associated genes is evaluated by comparing against the results of a recent genome wide association study for common variable immunodeficiency (CVID). Results: Our approach is able to prioritize genes associated with immunodeficiency in general (area under the ROC curve = 0.713) and CVID in particular (area under the ROC curve = 0.643). Conclusions: This approach may be used to investigate a larger range of failures of the immune system. Our method may be extended to other disease processes, using RNA levels to prioritize genes likely to contain disease associated DNA variants.