我们进行了一系列综合分析，包括肾细胞癌（RCC）的全转录组关联研究（TWAS）和全蛋白质组关联研究（PWAS），以提名和优先考虑实验室研究的分子靶标。基于对 29,020 名受影响个体和 835,670 名对照个体进行的全基因组关联研究 (GWAS) 以及在转录组学参考模型中训练的预测模型，我们的 TWAS 涵盖四个肾脏转录组（GTEx 肾皮质、肾小管、TCGA-KIRC [癌症] Genome Atlas 肾透明细胞癌]和 TCGA-KIRP [TCGA 肾肾乳头状细胞癌]）在四个转录组组中的至少两个中鉴定出 38 个基因关联（错误发现率 <5%），并鉴定了 12 个基因独立于 GWAS 易感区域。结合 GTEx 中 48 个组织的 TWAS 关联进行分析，确定了可在肿瘤转录组中复制的 23 个其他基因的关联。对两种主要组织学类型（透明细胞肾细胞癌和乳头状肾细胞癌）的分析揭示了亚型特异性关联，尽管两种亚型至少有三个共同的基因关联。 PWAS 鉴定了 13 种相关蛋白，全部映射到 GWAS 显着位点。 TWAS 鉴定的基因富集于 RCC 肿瘤中的活性增强子或启动子区域以及相关细胞系中的缺氧诱导因子结合位点。利用基因表达相关性，常见癌症（乳腺癌和前列腺癌）和 RCC 危险因素（例如高血压和 BMI）显示出与 RCC 共有的遗传贡献。我们的工作确定了 RCC 易感性的潜在分子靶标，用于下游功能研究。由 Elsevier Inc. 出版。

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.Published by Elsevier Inc.