期刊
GENOME RESEARCH
卷 28, 期 11, 页码 1621-1635出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.233304.117
关键词
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资金
- Intramural Research Program (IRP) of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health (NIH)
- Cancer Research UK (CRUK) [C588/A19167]
- NIH [CA083115]
- Australian Research Council Fellowship
- Cancer Research UK Programme Awards [C588/A4994, C588/A10589]
- Cancer Research UK [C8216/A6129]
- US National Institutes of Health [R01 ROI CA83115]
- European Commission under the 6th Framework Programme [LSHC-CT-2006-018702]
- MRC [MR/L01629X/1] Funding Source: UKRI
- NATIONAL CANCER INSTITUTE [R01CA083115, R01CA133996, P50CA093459, P50CA097007] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZIBHG000196] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES011740] Funding Source: NIH RePORTER
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.
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