RT Journal
A1 Zhang, Tongwu
A1 Choi, Jiyeon
A1 Kovacs, Michael A.
A1 Shi, Jianxin
A1 Xu, Mai
A1 NISC Comparative Sequencing Program
A1 Melanoma Meta-Analysis Consortium
A1 Goldstein, Alisa M.
A1 Trower, Adam J.
A1 Bishop, D. Timothy
A1 Iles, Mark M.
A1 Duffy, David L.
A1 MacGregor, Stuart
A1 Amundadottir, Laufey T.
A1 Law, Matthew H.
A1 Loftus, Stacie K.
A1 Pavan, William J.
A1 Brown, Kevin M.
T1 Cell-type–specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes
JF Genome Research 
JO Genome Research 
YR 2018 
FD November 01 
VO 28 
IS 11 
SP 1621 
OP 1635 
DO 10.1101/gr.233304.117 
UL http://genome.cshlp.org/content/28/11/1621.abstract 
AB Most expression quantitative trait locus (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 <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR < 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans-eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis-regulation of IRF4. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility 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.