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PMID |
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TITLE |
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Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. |
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ABSTRACT |
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The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis. |
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DATE PUBLISHED |
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HISTORY |
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PUBSTATUS |
PUBSTATUSDATE |
received |
2017/08/03 |
accepted |
2018/09/13 |
entrez |
2018/11/16 06:00 |
pubmed |
2018/11/16 06:00 |
medline |
2019/04/16 06:00 |
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AUTHORS |
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NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
Duffy DL |
|
Duffy |
David L |
DL |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. David.Duffy@qimrberghofer.edu.au. |
Zhu G |
|
Zhu |
Gu |
G |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
Li X |
|
Li |
Xin |
X |
|
Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, 63110, USA. |
Sanna M |
|
Sanna |
Marianna |
M |
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Department of Twin Research & Genetic Epidemiology, St Thomas Hospital Campus, Kings College, London, UK. |
Iles MM |
|
Iles |
Mark M |
MM |
|
Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. |
Jacobs LC |
|
Jacobs |
Leonie C |
LC |
|
Department of Dermatology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. |
Evans DM |
|
Evans |
David M |
DM |
|
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. |
Yazar S |
|
Yazar |
Seyhan |
S |
|
Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Australia. |
Beesley J |
|
Beesley |
Jonathan |
J |
|
QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
Law MH |
|
Law |
Matthew H |
MH |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
Kraft P |
|
Kraft |
Peter |
P |
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA. |
Visconti A |
|
Visconti |
Alessia |
A |
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Department of Twin Research & Genetic Epidemiology, St Thomas Hospital Campus, Kings College, London, UK. |
Taylor JC |
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Taylor |
John C |
JC |
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Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. |
Liu F |
|
Liu |
Fan |
F |
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Department of Genetic Identification, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. |
Wright MJ |
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Wright |
Margaret J |
MJ |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
Henders AK |
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Henders |
Anjali K |
AK |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
Bowdler L |
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Bowdler |
Lisa |
L |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
Glass D |
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Glass |
Dan |
D |
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Department of Twin Research & Genetic Epidemiology, St Thomas Hospital Campus, Kings College, London, UK. |
Ikram MA |
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Ikram |
M Arfan |
MA |
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Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands. |
Uitterlinden AG |
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Uitterlinden |
André G |
AG |
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Department of Internal Medicine, Erasmus MC, Rotterdam, Netherlands. |
Madden PA |
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Madden |
Pamela A |
PA |
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Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA. |
Heath AC |
|
Heath |
Andrew C |
AC |
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Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA. |
Nelson EC |
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Nelson |
Elliot C |
EC |
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Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA. |
Green AC |
|
Green |
Adele C |
AC |
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Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester, UK. |
Chanock S |
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Chanock |
Stephen |
S |
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Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. |
Barrett JH |
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Barrett |
Jennifer H |
JH |
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Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. |
Brown MA |
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Brown |
Matthew A |
MA |
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University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. |
Hayward NK |
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Hayward |
Nicholas K |
NK |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
MacGregor S |
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MacGregor |
Stuart |
S |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
Sturm RA |
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Sturm |
Richard A |
RA |
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Dermatology Research Centre, University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. |
Hewitt AW |
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Hewitt |
Alex W |
AW |
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Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Australia. |
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Melanoma GWAS Consortium |
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Kayser M |
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Kayser |
Manfred |
M |
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Department of Genetic Identification, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. |
Hunter DJ |
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Hunter |
David J |
DJ |
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, USA. |
Newton Bishop JA |
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Newton Bishop |
Julia A |
JA |
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Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. |
Spector TD |
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Spector |
Timothy D |
TD |
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Department of Twin Research & Genetic Epidemiology, St Thomas Hospital Campus, Kings College, London, UK. |
Montgomery GW |
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Montgomery |
Grant W |
GW |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. |
Mackey DA |
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Mackey |
David A |
DA |
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Centre for Ophthalmology and Vision Science, University of Western Australia and the Lions Eye Institute, Perth, Australia. |
Smith GD |
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Smith |
George Davey |
GD |
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MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. |
Nijsten TE |
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Nijsten |
Tamar E |
TE |
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Department of Dermatology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands. |
Bishop DT |
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Bishop |
D Timothy |
DT |
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Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. |
Bataille V |
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Bataille |
Veronique |
V |
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Department of Twin Research & Genetic Epidemiology, St Thomas Hospital Campus, Kings College, London, UK. |
Falchi M |
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Falchi |
Mario |
M |
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Department of Twin Research & Genetic Epidemiology, St Thomas Hospital Campus, Kings College, London, UK. |
Han J |
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Han |
Jiali |
J |
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Department of Epidemiology, Richard M. Fairbanks School of Public Health, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN, 63110, USA. |
Martin NG |
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Martin |
Nicholas G |
NG |
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QIMR Berghofer Medical Research Institute, Brisbane, Australia. |
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INVESTIGATORS |
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LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
Lee |
Jeffrey E |
JE |
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Brossard |
Myriam |
M |
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Moses |
Eric K |
EK |
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Song |
Fengju |
F |
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Kumar |
Rajiv |
R |
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Easton |
Douglas F |
DF |
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Pharoah |
Paul D P |
PDP |
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Swerdlow |
Anthony J |
AJ |
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Kypreou |
Katerina P |
KP |
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Harland |
Mark |
M |
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Randerson-Moor |
Juliette |
J |
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Akslen |
Lars A |
LA |
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Andresen |
Per A |
PA |
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Avril |
Marie-Françoise |
MF |
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Azizi |
Esther |
E |
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Scarrà |
Giovanna Bianchi |
GB |
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Brown |
Kevin M |
KM |
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Dębniak |
Tadeusz |
T |
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Elder |
David E |
DE |
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Fang |
Shenying |
S |
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Friedman |
Eitan |
E |
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Galan |
Pilar |
P |
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Ghiorzo |
Paola |
P |
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Gillanders |
Elizabeth M |
EM |
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Goldstein |
Alisa M |
AM |
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Gruis |
Nelleke A |
NA |
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Hansson |
Johan |
J |
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Helsing |
Per |
P |
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Hočevar |
Marko |
M |
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Höiom |
Veronica |
V |
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Ingvar |
Christian |
C |
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Kanetsky |
Peter A |
PA |
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Chen |
Wei V |
WV |
|
Landi |
Maria Teresa |
MT |
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Lang |
Julie |
J |
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Lathrop |
G Mark |
GM |
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Lubiński |
Jan |
J |
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Mackie |
Rona M |
RM |
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Mann |
Graham J |
GJ |
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Molven |
Anders |
A |
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Novaković |
Srdjan |
S |
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Olsson |
Håkan |
H |
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Puig |
Susana |
S |
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Puig-Butille |
Joan Anton |
JA |
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Radford-Smith |
Graham L |
GL |
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van der Stoep |
Nienke |
N |
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van Doorn |
Remco |
R |
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Whiteman |
David C |
DC |
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Craig |
Jamie E |
JE |
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Schadendorf |
Dirk |
D |
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Simms |
Lisa A |
LA |
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Burdon |
Kathryn P |
KP |
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Nyholt |
Dale R |
DR |
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Pooley |
Karen A |
KA |
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Orr |
Nicholas |
N |
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Stratigos |
Alexander J |
AJ |
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Cust |
Anne E |
AE |
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Ward |
Sarah V |
SV |
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Schulze |
Hans-Joachim |
HJ |
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Dunning |
Alison M |
AM |
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Demenais |
Florence |
F |
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Amos |
Christopher I |
CI |
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JOURNAL |
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VOLUME: 9 |
ISSUE: 1 |
TITLE: Nature communications |
ISOABBREVIATION: Nat Commun |
YEAR: 2018 |
MONTH: 11 |
DAY: 14 |
MEDLINEDATE: |
SEASON: |
CITEDMEDIUM: Internet |
ISSN: 2041-1723 |
ISSNTYPE: Electronic |
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MEDLINE JOURNAL |
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MEDLINETA: Nat Commun |
COUNTRY: England |
ISSNLINKING: 2041-1723 |
NLMUNIQUEID: 101528555 |
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PUBLICATION TYPE |
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PUBLICATIONTYPE TEXT |
Journal Article |
Meta-Analysis |
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COMMENTS AND CORRECTIONS |
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REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
ErratumIn |
Nat Commun. 2019 Jan 14;10(1):299 |
30643134 |
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GRANTS |
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GRANTID |
AGENCY |
COUNTRY |
12-0023 |
Worldwide Cancer Research |
United Kingdom |
MC_UU_00011/1 |
Medical Research Council |
United Kingdom |
P30 CA008748 |
NCI NIH HHS |
United States |
MC_UU_12013/4 |
Medical Research Council |
United Kingdom |
10589 |
Cancer Research UK |
United Kingdom |
MR/L01629X/1 |
Medical Research Council |
United Kingdom |
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GENERAL NOTE |
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KEYWORDS |
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MESH HEADINGS |
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DESCRIPTORNAME |
QUALIFIERNAME |
Carrier Proteins |
genetics |
Cytochrome P-450 CYP1B1 |
genetics |
European Continental Ancestry Group |
genetics |
Genetic Pleiotropy |
genetics |
Genetic Predisposition to Disease |
genetics |
Genome-Wide Association Study |
genetics |
Group VI Phospholipases A2 |
genetics |
Guanine Nucleotide Exchange Factors |
genetics |
Histone Deacetylases |
genetics |
Humans |
genetics |
Interferon Regulatory Factors |
genetics |
Melanoma |
genetics |
MicroRNAs |
genetics |
Microfilament Proteins |
genetics |
Nerve Tissue Proteins |
genetics |
Nevus, Pigmented |
genetics |
Nuclear Proteins |
genetics |
Polymorphism, Single Nucleotide |
genetics |
RNA |
genetics |
RNA-Binding Proteins |
genetics |
Receptors, G-Protein-Coupled |
genetics |
Repressor Proteins |
genetics |
Skin Neoplasms |
genetics |
Stem Cell Factor |
genetics |
Telomerase |
genetics |
Telomere-Binding Proteins |
genetics |
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SUPPLEMENTARY MESH |
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GENE SYMBOLS |
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CHEMICALS |
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REGISTRYNUMBER |
NAMEOFSUBSTANCE |
0 |
Carrier Proteins |
0 |
DOCK8 protein, human |
0 |
GPRC5A protein, human |
0 |
Guanine Nucleotide Exchange Factors |
0 |
Interferon Regulatory Factors |
0 |
KITLG protein, human |
0 |
MIRN146 microRNA, human |
0 |
MicroRNAs |
0 |
Microfilament Proteins |
0 |
Nerve Tissue Proteins |
0 |
Nuclear Proteins |
0 |
PPARGC1B protein, human |
0 |
RNA-Binding Proteins |
0 |
Receptors, G-Protein-Coupled |
0 |
Repressor Proteins |
0 |
SYNE2 protein, human |
0 |
Stem Cell Factor |
0 |
Stn1 protein, human |
0 |
Telomere-Binding Proteins |
0 |
interferon regulatory factor-4 |
0 |
telomerase RNA |
63231-63-0 |
RNA |
EC 1.14.14.1 |
CYP1B1 protein, human |
EC 1.14.14.1 |
Cytochrome P-450 CYP1B1 |
EC 2.7.7.49 |
Telomerase |
EC 3.1.1.4 |
Group VI Phospholipases A2 |
EC 3.1.1.4 |
PLA2G6 protein, human |
EC 3.5.1.98 |
HDAC4 protein, human |
EC 3.5.1.98 |
Histone Deacetylases |
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OTHER ID's |
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