i-GSEA4GWAS: a web server for identification of pathways/gene sets associated with traits by applying an improved gene set enrichment analysis to genome-wide association study

Zhang, Kunlin; Cui, Sijia; Chang, Suhua; Zhang, Liuyan; Wang, Jing

(FDR = 0.009), 'inflampathway' (FDR = 0.010), and 'cskpathway' (FDR = 0.011) have been replicated in our follow-up work of the initial GWAS by either the top hits or using GSEA (9) . Both the pathways 'ribosome' and 'st myocyte ad pathway' were only identified by i-GSEA (FDR < 0.05) and were not replicated by the follow-up GWAS and GSEA analysis. However, both pathways have references to support their relevance to HIV. For pathway 'ribosome' (FDR = 0.047), it has been known that the ribosomal frame shifting is a kind of gene expression mechanism of several RNA viruses (including HIV-1 and SARS-CoV) to express replicase enzymes and a couple of investigations have been carried out on this topic (25) (26) (27) . The pathway 'st myocyte ad pathway' (FDR = 0.040) contains a variety of adrenergic receptors that induce subtype-specific signaling effects. The top gene with the smallest P-value in this gene set, ITPR1 (inositol 1,4,5-triphosphate receptor, type 1), has been reported to interact with genes in HIV. For example HIV-1 Nef interacts with ITPR1 to trigger the activation of plasma membrane calcium influx channels (28); HIV-1 Tat induces release of calcium from ITPR1-regulated stores in neurons and astrocytes, an effect that plays an important role in Tat-induced TNF-a production (29) .