|
|
| PMID |
|
|
| TITLE |
|
| Cell-type-specific eQTL of primary melanocytes facilitates identification of melanoma susceptibility genes. |
|
| 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 -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 -eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through -regulation of Melanocyte eQTLs are enriched in -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 ( , , , , and ) were associated with melanoma at genome-wide significant -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. |
| © 2018 Zhang et al.; Published by Cold Spring Harbor Laboratory Press. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2017/12/07 |
| accepted |
2018/09/21 |
| pubmed |
2018/10/20 06:00 |
| medline |
2019/02/13 06:00 |
| entrez |
2018/10/19 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Zhang T |
|
Zhang |
Tongwu |
T |
|
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Choi J |
|
Choi |
Jiyeon |
J |
|
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Kovacs MA |
|
Kovacs |
Michael A |
MA |
|
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Shi J |
|
Shi |
Jianxin |
J |
|
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Xu M |
|
Xu |
Mai |
M |
|
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
|
NISC Comparative Sequencing Program |
|
|
|
|
|
|
Melanoma Meta-Analysis Consortium |
|
|
|
|
|
| Goldstein AM |
|
Goldstein |
Alisa M |
AM |
|
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Trower AJ |
|
Trower |
Adam J |
AJ |
|
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom. |
| Bishop DT |
|
Bishop |
D Timothy |
DT |
|
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom. |
| Iles MM |
|
Iles |
Mark M |
MM |
|
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom. |
| Duffy DL |
|
Duffy |
David L |
DL |
|
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia. |
| MacGregor S |
|
MacGregor |
Stuart |
S |
|
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia. |
| Amundadottir LT |
|
Amundadottir |
Laufey T |
LT |
|
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Law MH |
|
Law |
Matthew H |
MH |
|
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, 4006, Australia. |
| Loftus SK |
|
Loftus |
Stacie K |
SK |
|
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Pavan WJ |
|
Pavan |
William J |
WJ |
|
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
| Brown KM |
|
Brown |
Kevin M |
KM |
|
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. |
|
| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Law |
Matthew H |
MH |
|
| Bishop |
D Timothy |
DT |
|
| Lee |
Jeffrey E |
JE |
|
| Brossard |
Myriam |
M |
|
| Martin |
Nicholas G |
NG |
|
| Moses |
Eric K |
EK |
|
| Song |
Fengju |
F |
|
| Barrett |
Jennifer H |
JH |
|
| Kumar |
Rajiv |
R |
|
| Easton |
Douglas F |
DF |
|
| Pharoah |
Paul D P |
PDP |
|
| Swerdlow |
Anthony J |
AJ |
|
| Kypreou |
Katerina P |
KP |
|
| Taylor |
John C |
JC |
|
| Harland |
Mark |
M |
|
| Randerson-Moor |
Juliette |
J |
|
| Akslen |
Lars A |
LA |
|
| Andresen |
Per A |
PA |
|
| Avril |
Marie-Françoise |
MF |
|
| Azizi |
Esther |
E |
|
| Scarrà |
Giovanna Bianchi |
GB |
|
| Brown |
Kevin M |
KM |
|
| Dȩbniak |
Tadeusz |
T |
|
| Duffy |
David L |
DL |
|
| Elder |
David E |
DE |
|
| Fang |
Shenying |
S |
|
| Friedman |
Eitan |
E |
|
| Galan |
Pilar |
P |
|
| Ghiorzo |
Paola |
P |
|
| Gillanders |
Elizabeth M |
EM |
|
| Goldstein |
Alisa M |
AM |
|
| Gruis |
Nelleke A |
NA |
|
| Hansson |
Johan |
J |
|
| Helsing |
Per |
P |
|
| Hočevar |
Marko |
M |
|
| Höiom |
Veronica |
V |
|
| Ingvar |
Christian |
C |
|
| Kanetsky |
Peter A |
PA |
|
| Chen |
Wei V |
WV |
|
| Landi |
Maria Teresa |
MT |
|
| Lang |
Julie |
J |
|
| Lathrop |
G Mark |
GM |
|
| Lubiński |
Jan |
J |
|
| Mackie |
Rona M |
RM |
|
| Mann |
Graham J |
GJ |
|
| Molven |
Anders |
A |
|
| Montgomery |
Grant W |
GW |
|
| Novaković |
Srdjan |
S |
|
| Olsson |
Håkan |
H |
|
| Puig |
Susana |
S |
|
| Puig-Butille |
Joan Anton |
JA |
|
| Wu |
Wenting |
W |
|
| Qureshi |
Abrar A |
AA |
|
| Radford-Smith |
Graham L |
GL |
|
| van der Stoep |
Nienke |
N |
|
| van Doorn |
Remco |
R |
|
| Whiteman |
David C |
DC |
|
| Craig |
Jamie E |
JE |
|
| Schadendorf |
Dirk |
D |
|
| Simms |
Lisa A |
LA |
|
| Burdon |
Kathryn P |
KP |
|
| Nyholt |
Dale R |
DR |
|
| Pooley |
Karen A |
KA |
|
| Orr |
Nick |
N |
|
| Stratigos |
Alexander J |
AJ |
|
| Cust |
Anne E |
AE |
|
| Ward |
Sarah V |
SV |
|
| Hayward |
Nicholas K |
NK |
|
| Han |
Jiali |
J |
|
| Schulze |
Hans-Joachim |
HJ |
|
| Dunning |
Alison M |
AM |
|
| Bishop |
Julia A Newton |
JAN |
|
| Demenais |
Florence |
F |
|
| Amos |
Christopher I |
CI |
|
| MacGregor |
Stuart |
S |
|
| Iles |
Mark M |
MM |
|
| Barnabas |
Beatrice B |
BB |
|
| Bouffard |
Gerard G |
GG |
|
| Brooks |
Shelis Y |
SY |
|
| Coleman |
Holly |
H |
|
| Dekhtyar |
Lyudmila |
L |
|
| Guan |
Xiaobin |
X |
|
| Han |
Joel |
J |
|
| Ho |
Shi-Ling |
SL |
|
| Legaspi |
Richelle |
R |
|
| Maduro |
Quino L |
QL |
|
| Masiello |
Catherine A |
CA |
|
| McDowell |
Jennifer C |
JC |
|
| Montemayor |
Casandra |
C |
|
| Mullikin |
James C |
JC |
|
| Park |
Morgan |
M |
|
| Riebow |
Nancy L |
NL |
|
| Schandler |
Karen |
K |
|
| Schmidt |
Brian |
B |
|
| Sison |
Christina |
C |
|
| Smith |
Raymond |
R |
|
| Stantripop |
Sirintorn |
S |
|
| Thomas |
James W |
JW |
|
| Thomas |
Pamela J |
PJ |
|
| Vemulapalli |
Meghana |
M |
|
| Young |
Alice C |
AC |
|
|
| JOURNAL |
|
| VOLUME: 28 |
| ISSUE: 11 |
| TITLE: Genome research |
| ISOABBREVIATION: Genome Res |
| YEAR: 2018 |
| MONTH: 11 |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1549-5469 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Genome Res |
| COUNTRY: United States |
| ISSNLINKING: 1088-9051 |
| NLMUNIQUEID: 9518021 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, N.I.H., Intramural |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
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|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| R01 CA133996 |
NCI NIH HHS |
United States |
| R01 CA083115 |
NCI NIH HHS |
United States |
| P50 CA097007 |
NCI NIH HHS |
United States |
| C8216/A6129 |
Cancer Research UK |
United Kingdom |
| R01 ES011740 |
NIEHS NIH HHS |
United States |
| C588/A4994 |
Cancer Research UK |
United Kingdom |
| C588/A10589 |
Cancer Research UK |
United Kingdom |
| C490/A10124 |
Cancer Research UK |
United Kingdom |
| C588/A19167 |
Cancer Research UK |
United Kingdom |
| C1287/A10118 |
Cancer Research UK |
United Kingdom |
| P50 CA093459 |
NCI NIH HHS |
United States |
| 10589 |
Cancer Research UK |
United Kingdom |
| MR/L01629X/1 |
Medical Research Council |
United Kingdom |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Basic Helix-Loop-Helix Transcription Factors |
genetics |
| Carrier Proteins |
genetics |
| Cells, Cultured |
genetics |
| Genetic Predisposition to Disease |
genetics |
| Heme-Binding Proteins |
genetics |
| Hemeproteins |
genetics |
| Humans |
genetics |
| Interferon Regulatory Factors |
genetics |
| Linkage Disequilibrium |
genetics |
| Melanocytes |
metabolism |
| Melanoma |
genetics |
| Polymorphism, Single Nucleotide |
genetics |
| Quantitative Trait Loci |
genetics |
| Repressor Proteins |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
Basic Helix-Loop-Helix Transcription Factors |
| 0 |
Carrier Proteins |
| 0 |
HEBP1 protein, human |
| 0 |
Heme-Binding Proteins |
| 0 |
Hemeproteins |
| 0 |
Interferon Regulatory Factors |
| 0 |
MSC protein, human |
| 0 |
Repressor Proteins |
| 0 |
ZFP90 protein, human |
| 0 |
interferon regulatory factor-4 |
|
| OTHER ID's |
|
|
|
