Transcriptome- and proteome-wide association studies identify genes associated with renal cell carcinoma

Abstract

We performed a series of integrative analyses including transcriptome-wide association studies (TWASs) and proteome-wide association studies (PWASs) of renal cell carcinoma (RCC) to nominate and prioritize molecular targets for laboratory investigation. On the basis of a genome-wide association study (GWAS) of 29,020 affected individuals and 835,670 control individuals and prediction models trained in transcriptomic reference models, our TWAS across four kidney transcriptomes (GTEx kidney cortex, kidney tubules, TCGA-KIRC [The Cancer Genome Atlas kidney renal clear-cell carcinoma], and TCGA-KIRP [TCGA kidney renal papillary cell carcinoma]) identified 38 gene associations (false-discovery rate <5%) in at least two of four transcriptomic panels and identified 12 genes that were independent of GWAS susceptibility regions. Analyses combining TWAS associations across 48 tissues from GTEx identified associations that were replicable in tumor transcriptomes for 23 additional genes. Analyses by the two major histologic types (clear-cell RCC and papillary RCC) revealed subtype-specific associations, although at least three gene associations were common to both subtypes. PWAS identified 13 associated proteins, all mapping to GWAS-significant loci. TWAS-identified genes were enriched for active enhancer or promoter regions in RCC tumors and hypoxia-inducible factor binding sites in relevant cell lines. Using gene expression correlation, common cancers (breast and prostate) and RCC risk factors (e.g., hypertension and BMI) display genetic contributions shared with RCC. Our work identifies potential molecular targets for RCC susceptibility for downstream functional investigation.

Keywords: HIF; TWAS/PWAS; promoter/enhancer; renal cell carcinoma; subtypes; susceptibility genes.

Figure 1

Genome-wide summary of kidney-specific TWAS associations with RCC Manhattan plots showing the TWAS associations of overall RCC across the transcriptomes from (A) GTEx v.8 kidney cortex, (B) kidney tubule samples, (C) TCGA kidney renal clear-cell carcinoma (KIRC), and (D) TCGA kidney papillary cell carcinoma (KIRP). A dashed horizontal line denotes the corresponding Bonferroni correction threshold for each panel. An inset shows the corresponding pie charts for the number of genes that are independent of significant GWAS signals in each analysis.

Figure 2

Genes identified across multiple kidney-specific TWASs Upset plots showing the overlap of the genes identified to be associated to (A) RCC, (B) ccRCC, and (C) papRCC in kidney-specific TWASs with GTEx kidney cortex, kidney tubule, TCGA-KIRC, and TCGA-KIRP. The genes identified in the highest number of panels are mentioned and colored according to their proximity to GWAS-significant loci.

Figure 3

Genomic features of RCC-associated genes Regional plots for GWAS and conditional associations (GTEx kidney cortex) for the cis regions of (A) HLF and (B) PPIL3 (marked in green in the top panel). The bottom panel shows H3K27ac peaks in ccRCC tumors reported by Nassar et al. in the respective regions. (C) Overlap of ChIP-seq peaks across different HIF transcription-factor genes, cell lines, and replicates (on the rows) with the cis region of the high-priority RCC-associated genes.