Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes.
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Date
2018-11-01ICR Author
Author
Zhang, T
Choi, J
Kovacs, MA
Shi, J
Xu, M
NISC Comparative Sequencing Program,
Melanoma Meta-Analysis Consortium,
Goldstein, AM
Trower, AJ
Bishop, DT
Iles, MM
Duffy, DL
MacGregor, S
Amundadottir, LT
Law, MH
Loftus, SK
Pavan, WJ
Brown, KM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
NISC Comparative Sequencing Program
Melanoma Meta-Analysis Consortium
Cells, Cultured
Melanocytes
Humans
Melanoma
Genetic Predisposition to Disease
Carrier Proteins
Hemeproteins
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Interferon Regulatory Factors
Basic Helix-Loop-Helix Transcription Factors
Heme-Binding Proteins
Research team
Aetiological Epidemiology
Language
eng
Date accepted
2018-09-21
License start date
2018-11
Citation
Genome research, 2018, 28 (11), pp. 1621 - 1635
Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT