A novel method to identify cell-type specific regulatory variants and their role in cancer risk

Background Expression quantitative trait loci (eQTLs) have been crucial in providing an understanding of how genetic variants influence gene expression. However, eQTLs are known to exert cell type specific effects, and existing methods to identify cell type specific QTLs in bulk data require large sample sizes. Results Here, we propose DeCAF (DEconvoluted cell type Allele specific Function), a new method to identify cell-fraction (cf) QTLs in tumors by leveraging both allelic and total expression information. Applying DeCAF to RNA-seq data from TCGA, we identified 3,664 genes with cfQTLs (at 10% FDR) in 14 cell types, a 5.63x increase in discovery over conventional interaction-eQTL mapping. cfQTLs replicated in external cell type specific eQTL data and were more enriched for cancer risk than conventional eQTLs. The intersection of tumorspecific QTL effects (tsQTLs) with GWAS loci identified rs4765621 and SCARB1 , which has been previously linked to renal cell carcinoma (RCC) progression and experimentally validated in tumors. Conclusions Our new method, DeCAF, empowers the discovery of biologically meaningful cfQTLs from bulk RNA-seq data in moderately sized studies. Our study contributes to a better understanding of germline mechanisms underlying the anticancer immune response as well as cfQTLs contributing to cancer risk.