P-values of initially top-ranked pathways after removal of significant genes.

(A) P-value after removal of most significant gene for pathways demonstrating p < 10−12 across each of three phenotypes. We only show the original top 500 pathways in each phenotype for sake of presentation. (B) Percentage of pathways with original significance p < 10−12 passing Bonferroni-corrected significance threshold after top significant gene is removed, stratified by quantile of gene set size. (C) P-value after removal of three most significant genes for top 500 pathways across each of three phenotypes. (D) P-value of Gene Ontology Ear Morphogenesis and Nature Pathway Interaction Database TRAIL Signaling pathways as most significant genes are removed one by one (for association with breast cancer only). P-values less than 10−12 are truncated at this value. It appears that many of the most significant height pathways are driven to significance by multiple highly associated genes, while the opposite is true for breast cancer.