| Title: | Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes |
| Journal: | Genome Research |
| Published: | 17 Oct 2018 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/30333196/ |
| DOI: | https://doi.org/10.1101/gr.233304.117 |
| URL: | http://genome.cshlp.org/content/28/11/1621.full.pdf |
| Citations: | 70 (12 in last 2 years) as of 8 Aug 2024 |
Publication 12915
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Abstract
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.</p>
14 Keywords
- Basic Helix-Loop-Helix Transcription Factors
- Carrier Proteins
- Cells, Cultured
- Genetic Predisposition to Disease
- Heme-Binding Proteins
- Hemeproteins
- Humans
- Interferon Regulatory Factors
- Linkage Disequilibrium
- Melanocytes
- Melanoma
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- Repressor Proteins
119 Authors
- Tongwu Zhang
- Jiyeon Choi
- Michael A. Kovacs
- Jianxin Shi
- Mai Xu
- NISC Comparative Sequencing Program
- Melanoma Meta-Analysis Consortium
- Alisa M. Goldstein
- Adam J. Trower
- D. Timothy Bishop
- Mark M. Iles
- David L. Duffy
- Stuart MacGregor
- Laufey T. Amundadottir
- Matthew H. Law
- Stacie K. Loftus
- William J. Pavan
- Kevin M. Brown
- Matthew H. Law
- D. Timothy Bishop
- Jeffrey E. Lee
- Myriam Brossard
- Nicholas G. Martin
- Eric K. Moses
- Fengju Song
- Jennifer H. Barrett
- Rajiv Kumar
- Douglas F. Easton
- Paul D.P. Pharoah
- Anthony J. Swerdlow
- Katerina P. Kypreou
- John C. Taylor
- Mark Harland
- Juliette Randerson-Moor
- Lars A. Akslen
- Per A. Andresen
- Marie-Françoise Avril
- Esther Azizi
- Giovanna Bianchi Scarrà
- Kevin M. Brown
- Tadeusz Dȩbniak
- David L. Duffy
- David E. Elder
- Shenying Fang
- Eitan Friedman
- Pilar Galan
- Paola Ghiorzo
- Elizabeth M. Gillanders
- Alisa M. Goldstein
- Nelleke A. Gruis
- Johan Hansson
- Per Helsing
- Marko Hočevar
- Veronica Höiom
- Christian Ingvar
- Peter A. Kanetsky
- Wei V. Chen
- Maria Teresa Landi
- Julie Lang
- G. Mark Lathrop
- Jan Lubiński
- Rona M. Mackie
- Graham J. Mann
- Anders Molven
- Grant W. Montgomery
- Srdjan Novaković
- Håkan Olsson
- Susana Puig
- Joan Anton Puig-Butille
- Wenting Wu
- Abrar A. Qureshi
- Graham L. Radford-Smith
- Nienke van der Stoep
- Remco van Doorn
- David C. Whiteman
- Jamie E. Craig
- Dirk Schadendorf
- Lisa A. Simms
- Kathryn P. Burdon
- Dale R. Nyholt
- Karen A. Pooley
- Nick Orr
- Alexander J. Stratigos
- Anne E. Cust
- Sarah V. Ward
- Nicholas K. Hayward
- Jiali Han
- Hans-Joachim Schulze
- Alison M. Dunning
- Julia A. Newton Bishop
- Florence Demenais
- Christopher I. Amos
- Stuart MacGregor
- Mark M. Iles
- Beatrice B. Barnabas
- Gerard G. Bouffard
- Shelis Y. Brooks
- Holly Coleman
- Lyudmila Dekhtyar
- Xiaobin Guan
- Joel Han
- Shi-ling Ho
- Richelle Legaspi
- Quino L. Maduro
- Catherine A. Masiello
- Jennifer C. McDowell
- Casandra Montemayor
- James C. Mullikin
- Morgan Park
- Nancy L. Riebow
- Karen Schandler
- Brian Schmidt
- Christina Sison
- Raymond Smith
- Sirintorn Stantripop
- James W. Thomas
- Pamela J. Thomas
- Meghana Vemulapalli
- Alice C. Young
1 Application
| Application ID | Title |
|---|---|
| 3071 | Genetic epidemiology of melanoma and melanoma survival |
Enabling scientific discoveries that improve human health