Figure 6
Sub-threshold RCC-associated GWAS loci are enriched at HIF-binding sites and for proximity to HIF-induced genes. Sub-threshold RCC-associated loci were defined as independent GWAS loci at which the index SNP failed to reach genome-wide significance (5 ×10−8 ≤ p ≤ 1 ×10−4). (A) The number overlapping (red arrows) with HIF-binding sites together with the expected overlap (blue bars) was determined as for Fig. 1. (B) The converse bootstrapping approach was used in which HIF-binding sites were randomly shuffled but constrained to regions defined as active enhancers. (C) The number of sub-threshold loci either overlapping or lying within 25 kb of a HIF-binding site, together with the expected frequency distribution. (D) RNA-seq analysis (n = 3) of 786-O cells (stably transfected with wild-type VHL) was used to rank all measurable genes according to their regulation (combined fold-change and p-value) by VHL/HIF (x-axis). The three closest genes to each sub-threshold GWAS locus are illustrated as vertical bars. Weighted gene set enrichment analysis (green line) showed significant enrichment of this gene set amongst upregulated, but not down regulated genes (p = 0.01).
