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

The i-GSEA4GWAS web server implements i-GSEA to help researchers explore GWAS data efficiently. i-GSEA is an application and extension of GSEA. For GSEA, it runs the following three key procedures. (i) The max statistics or Àlog(P-value) of closely spaced SNPs in a gene is used to represent the gene; then, the ranked gene list with corresponding representing values is utilized to calculate each gene set's enrichment score (ES), i.e. a Kolmogorov-Smirnov like statistics with weight 1, which reflects the trend that genes of a gene set tend to be located at the top of the entire ranked genome-wide gene list. (ii) The phenotype label permutation (to break the association between genotype and phenotype) and a straightforward normalization are performed to generate the distribution of the ES and correct gene variation (i.e. different genes with different number of SNPs mapped will result in identification of gene sets containing genes with more SNPs mapped, instead of genes with functional correlation) and gene set variation (i.e. different gene sets contain different number of genes) (3). (iii) Based on all the distributions of ESs generated by permutation, false discovery rate (FDR) is used for multiple testing correction (17) .