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PMID |
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TITLE |
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Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis. |
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ABSTRACT |
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Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10 ) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis. |
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DATE PUBLISHED |
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HISTORY |
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PUBSTATUS |
PUBSTATUSDATE |
received |
2019/02/28 |
accepted |
2019/09/10 |
entrez |
2019/10/26 06:00 |
pubmed |
2019/10/28 06:00 |
medline |
2020/02/06 06:00 |
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AUTHORS |
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NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
Gallagher CS |
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Gallagher |
C S |
CS |
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Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA. |
Mäkinen N |
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Mäkinen |
N |
N |
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Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. netta_makinen@dfci.harvard.edu. |
Harris HR |
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Harris |
H R |
HR |
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Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. |
Rahmioglu N |
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Rahmioglu |
N |
N |
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Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK. |
Uimari O |
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Uimari |
O |
O |
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Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90220, Oulu, Finland. |
Cook JP |
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Cook |
J P |
JP |
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Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK. |
Shigesi N |
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Shigesi |
N |
N |
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Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. |
Ferreira T |
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Ferreira |
T |
T |
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Big Data Institute, Li Ka Shing Center for Health Information and Discovery, Oxford University, Oxford, OX3 7LF, UK. |
Velez-Edwards DR |
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Velez-Edwards |
D R |
DR |
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Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, 37203, USA. |
Edwards TL |
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Edwards |
T L |
TL |
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Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, 37203, USA. |
Mortlock S |
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Mortlock |
S |
S |
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Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, 4072, Australia. |
Ruhioglu Z |
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Ruhioglu |
Z |
Z |
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Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. |
Day F |
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Day |
F |
F |
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MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. |
Becker CM |
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Becker |
C M |
CM |
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Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. |
Karhunen V |
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Karhunen |
V |
V |
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Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, W2 1PG, UK. |
Martikainen H |
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Martikainen |
H |
H |
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Department of Obstetrics and Gynecology, Oulu University Hospital and PEDEGO Research Unit & Medical Research Center Oulu, University of Oulu and Oulu University Hospital, 90220, Oulu, Finland. |
Järvelin MR |
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Järvelin |
M-R |
MR |
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Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, Middlesex, UB8 3PH, UK. |
Cantor RM |
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Cantor |
R M |
RM |
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Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90095, USA. |
Ridker PM |
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Ridker |
P M |
PM |
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Division of Preventative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. |
Terry KL |
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Terry |
K L |
KL |
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Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. |
Buring JE |
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Buring |
J E |
JE |
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Division of Preventative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. |
Gordon SD |
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Gordon |
S D |
SD |
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Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
Medland SE |
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Medland |
S E |
SE |
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Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
Montgomery GW |
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Montgomery |
G W |
GW |
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Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
Nyholt DR |
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Nyholt |
D R |
DR |
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Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia. |
Hinds DA |
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Hinds |
D A |
DA |
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23andMe, Mountain View, CA, 94041, USA. |
Tung JY |
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Tung |
J Y |
JY |
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23andMe, Mountain View, CA, 94041, USA. |
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23andMe Research Team |
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Perry JRB |
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Perry |
J R B |
JRB |
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MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. |
Lind PA |
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Lind |
P A |
PA |
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Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
Painter JN |
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Painter |
J N |
JN |
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Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
Martin NG |
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Martin |
N G |
NG |
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Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. |
Morris AP |
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Morris |
A P |
AP |
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Department of Biostatistics, University of Liverpool, Liverpool, L69 3GL, UK. |
Chasman DI |
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Chasman |
D I |
DI |
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Division of Preventative Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. |
Missmer SA |
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Missmer |
S A |
SA |
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Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA. |
Zondervan KT |
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Zondervan |
K T |
KT |
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Endometriosis CaRe Centre, Nuffield Department of Women's and Reproductive Health, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU, UK. |
Morton CC |
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Morton |
C C |
CC |
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Manchester Centre for Audiology and Deafness, Manchester Academic Health Science Center, University of Manchester, Manchester, M13 9PL, UK. cmorton@bwh.harvard.edu. |
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INVESTIGATORS |
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LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
Agee |
Michelle |
M |
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Alipanahi |
Babak |
B |
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Auton |
Adam |
A |
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Bell |
Robert K |
RK |
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Bryc |
Katarzyna |
K |
|
Elson |
Sarah L |
SL |
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Fontanillas |
Pierre |
P |
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Furlotte |
Nicholas A |
NA |
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Huber |
Karen E |
KE |
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Kleinman |
Aaron |
A |
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Litterman |
Nadia K |
NK |
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McIntyre |
Matthew H |
MH |
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Mountain |
Joanna L |
JL |
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Noblin |
Elizabeth S |
ES |
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Northover |
Carrie A M |
CAM |
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Pitts |
Steven J |
SJ |
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Sathirapongsasuti |
J Fah |
JF |
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Sazonova |
Olga V |
OV |
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Shelton |
Janie F |
JF |
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Shringarpure |
Suyash |
S |
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Tian |
Chao |
C |
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Vacic |
Vladimir |
V |
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Wilson |
Catherine H |
CH |
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JOURNAL |
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VOLUME: 10 |
ISSUE: 1 |
TITLE: Nature communications |
ISOABBREVIATION: Nat Commun |
YEAR: 2019 |
MONTH: 10 |
DAY: 24 |
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 |
Research Support, N.I.H., Extramural |
Research Support, Non-U.S. Gov't |
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COMMENTS AND CORRECTIONS |
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GRANTS |
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GENERAL NOTE |
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KEYWORDS |
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MESH HEADINGS |
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DESCRIPTORNAME |
QUALIFIERNAME |
Adult |
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Ataxia Telangiectasia Mutated Proteins |
genetics |
Endometriosis |
genetics |
European Continental Ancestry Group |
genetics |
Female |
genetics |
Forkhead Box Protein O1 |
metabolism |
Genome-Wide Association Study |
metabolism |
Humans |
metabolism |
Leiomyoma |
genetics |
Mendelian Randomization Analysis |
genetics |
Menorrhagia |
etiology |
Middle Aged |
etiology |
Polymorphism, Single Nucleotide |
etiology |
Proportional Hazards Models |
etiology |
Receptor, Fibroblast Growth Factor, Type 4 |
genetics |
Signal Transduction |
genetics |
Telomerase |
genetics |
Uterine Neoplasms |
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 |
FOXO1 protein, human |
0 |
Forkhead Box Protein O1 |
EC 2.7.10.1 |
FGFR4 protein, human |
EC 2.7.10.1 |
Receptor, Fibroblast Growth Factor, Type 4 |
EC 2.7.11.1 |
ATM protein, human |
EC 2.7.11.1 |
Ataxia Telangiectasia Mutated Proteins |
EC 2.7.7.49 |
TERT protein, human |
EC 2.7.7.49 |
Telomerase |
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OTHER ID's |
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