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

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.