Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes.

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type specific regulatory landscape of human melanocytes, which give rise to melanoma but account for cis-eQTL SNPs prior to LD-pruning and 4,997 eGenes (FDR trans -eQTLs with a pigmentation-associated SNP for four genes, likely through its cis -regulation of IRF4 , encoding a transcription factor implicated in human pigmentation phenotypes. Melanocyte eQTLs are enriched in cis -regulatory signatures found in melanocytes as well as melanoma-associated variants identified through genome-wide association studies (GWAS). Co-localization of melanoma GWAS variants and eQTLs from melanocyte and skin eQTL datasets identified candidate melanoma susceptibility genes for six known GWAS loci including unique genes identified by the melanocyte dataset. Further, a transcriptome-wide association study using published melanoma GWAS data uncovered four new loci, where imputed expression levels of five genes ( ZFP90 , HEBP1 , MSC , CBWD1 , and RP11-383H13.1 ) were associated with melanoma at genome-wide significant P -values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings and present a robust database for genomic research of melanoma risk and melanocyte biology.