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PMID |
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TITLE |
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The genetic architecture of sporadic and multiple consecutive miscarriage. |
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ABSTRACT |
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Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10 , odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10 , OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10 , OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10 , OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication. |
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DATE PUBLISHED |
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HISTORY |
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PUBSTATUS |
PUBSTATUSDATE |
received |
2019/09/16 |
accepted |
2020/10/23 |
entrez |
2020/11/26 05:40 |
pubmed |
2020/11/27 06:00 |
medline |
2020/12/15 06:00 |
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AUTHORS |
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NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
Laisk T |
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Laisk |
Triin |
T |
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Competence Centre on Health Technologies, Tartu, Estonia. triin.laisk@ut.ee. |
Soares ALG |
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Soares |
Ana Luiza G |
ALG |
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Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. |
Ferreira T |
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Ferreira |
Teresa |
T |
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Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK. |
Painter JN |
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Painter |
Jodie N |
JN |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
Censin JC |
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Censin |
Jenny C |
JC |
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Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. |
Laber S |
|
Laber |
Samantha |
S |
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Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. |
Bacelis J |
|
Bacelis |
Jonas |
J |
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Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden. |
Chen CY |
|
Chen |
Chia-Yen |
CY |
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Broad Institute of MIT and Harvard, Cambridge, MA, USA. |
Lepamets M |
|
Lepamets |
Maarja |
M |
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Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. |
Lin K |
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Lin |
Kuang |
K |
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Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK. |
Liu S |
|
Liu |
Siyang |
S |
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Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark. |
Millwood IY |
|
Millwood |
Iona Y |
IY |
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Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK. |
Ramu A |
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Ramu |
Avinash |
A |
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Department of Genetics, Washington University in St. Louis, Saint Louis, MO, USA. |
Southcombe J |
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Southcombe |
Jennifer |
J |
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Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK. |
Andersen MS |
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Andersen |
Marianne S |
MS |
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Department of Endocrinology, Odense University Hospital, Odense, Denmark. |
Yang L |
|
Yang |
Ling |
L |
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Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK. |
Becker CM |
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Becker |
Christian M |
CM |
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Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK. |
Børglum AD |
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Børglum |
Anders D |
AD |
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Center for Genomics and Personalized Medicine, Aarhus University and University Hospital, Aarhus, Denmark. |
Gordon SD |
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Gordon |
Scott D |
SD |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
Bybjerg-Grauholm J |
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Bybjerg-Grauholm |
Jonas |
J |
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Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. |
Helgeland Ø |
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Helgeland |
Øyvind |
Ø |
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KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway. |
Hougaard DM |
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Hougaard |
David M |
DM |
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Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark. |
Jin X |
|
Jin |
Xin |
X |
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School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China. |
Johansson S |
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Johansson |
Stefan |
S |
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Department of Medical Genetics, Haukeland University Hospital, N-5021, Bergen, Norway. |
Juodakis J |
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Juodakis |
Julius |
J |
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Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. |
Kartsonaki C |
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Kartsonaki |
Christiana |
C |
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Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK. |
Kukushkina V |
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Kukushkina |
Viktorija |
V |
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Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. |
Lind PA |
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Lind |
Penelope A |
PA |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
Metspalu A |
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Metspalu |
Andres |
A |
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Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia. |
Montgomery GW |
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Montgomery |
Grant W |
GW |
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University of Queensland, St Lucia, QLD, Australia. |
Morris AP |
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Morris |
Andrew P |
AP |
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Department of Biostatistics, University of Liverpool, Liverpool, UK. |
Mors O |
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Mors |
Ole |
O |
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Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark. |
Mortensen PB |
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Mortensen |
Preben B |
PB |
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National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark. |
Njølstad PR |
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Njølstad |
Pål R |
PR |
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Department of Pediatrics, Haukeland University Hospital, Bergen, Norway. |
Nordentoft M |
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Nordentoft |
Merete |
M |
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Copenhagen University Hospital, Mental Health Center Copenhagen, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark. |
Nyholt DR |
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Nyholt |
Dale R |
DR |
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School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia. |
Lippincott M |
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Lippincott |
Margaret |
M |
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Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA. |
Seminara S |
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Seminara |
Stephanie |
S |
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Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA. |
Salumets A |
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Salumets |
Andres |
A |
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Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. |
Snieder H |
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Snieder |
Harold |
H |
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Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. |
Zondervan K |
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Zondervan |
Krina |
K |
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Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK. |
Werge T |
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Werge |
Thomas |
T |
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Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. |
Chen Z |
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Chen |
Zhengming |
Z |
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Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK. |
Conrad DF |
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Conrad |
Donald F |
DF |
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Department of Genetics, Washington University in St. Louis, Saint Louis, MO, USA. |
Jacobsson B |
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Jacobsson |
Bo |
B |
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Department of Genetics and Bioinformatics, Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway. |
Li L |
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Li |
Liming |
L |
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Department of Epidemiology & Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China. |
Martin NG |
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Martin |
Nicholas G |
NG |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
Neale BM |
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Neale |
Benjamin M |
BM |
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Broad Institute of MIT and Harvard, Cambridge, MA, USA. |
Nielsen R |
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Nielsen |
Rasmus |
R |
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Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark. |
Walters RG |
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Walters |
Robin G |
RG |
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Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK. |
Granne I |
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Granne |
Ingrid |
I |
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Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK. |
Medland SE |
|
Medland |
Sarah E |
SE |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
Mägi R |
|
Mägi |
Reedik |
R |
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Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia. |
Lawlor DA |
|
Lawlor |
Deborah A |
DA |
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Bristol National Institute of Health Research Biomedical Research Centre, Bristol, UK. |
Lindgren CM |
|
Lindgren |
Cecilia M |
CM |
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Program in Medical and Population Genetics, Broad Institute, Boston, MA, USA. cecilia.lindgren@bdi.ox.ac.uk. |
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INVESTIGATORS |
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JOURNAL |
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VOLUME: 11 |
ISSUE: 1 |
TITLE: Nature communications |
ISOABBREVIATION: Nat Commun |
YEAR: 2020 |
MONTH: 11 |
DAY: 25 |
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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GRANTID |
AGENCY |
COUNTRY |
N01ES75558 |
NIEHS NIH HHS |
United States |
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British Heart Foundation |
United Kingdom |
MC_QA137853 |
Medical Research Council |
United Kingdom |
WT088806 |
Wellcome Trust |
United Kingdom |
MC-PC-13049 |
Medical Research Council |
United Kingdom |
MC_UU_12026/2 |
Medical Research Council |
United Kingdom |
U01 HG004424 |
NHGRI NIH HHS |
United States |
N02 HL64278 |
NHLBI NIH HHS |
United States |
HHSN268201600002C |
NHLBI NIH HHS |
United States |
HHSN268201600004C |
NHLBI NIH HHS |
United States |
MC_UU_00011/6 |
Medical Research Council |
United Kingdom |
MC_PC_17228 |
Medical Research Council |
United Kingdom |
U01 HG005152 |
NHGRI NIH HHS |
United States |
MC_U137686851 |
Medical Research Council |
United Kingdom |
HHSN268201600001C |
NHLBI NIH HHS |
United States |
P51 OD011092 |
NIH HHS |
United States |
HHSN268201600003C |
NHLBI NIH HHS |
United States |
203141/Z/16/Z |
Wellcome Trust |
United Kingdom |
|
Department of Health |
United Kingdom |
202922/Z/16/Z |
Wellcome Trust |
United Kingdom |
MC-PC-14135 |
Medical Research Council |
United Kingdom |
MC_PC_14135 |
Medical Research Council |
United Kingdom |
MC_PC_15018 |
Medical Research Council |
United Kingdom |
HHSN268201600018C |
NHLBI NIH HHS |
United States |
MC_UU_00017/1 |
Medical Research Council |
United Kingdom |
088158/Z/09/Z |
Wellcome Trust |
United Kingdom |
U01 HG005157 |
NHGRI NIH HHS |
United States |
102215/2/13/2 |
Wellcome Trust |
United Kingdom |
104085/Z/14/Z |
Wellcome Trust |
United Kingdom |
G9815508 |
Medical Research Council |
United Kingdom |
MC_PC_13049 |
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 |
Abortion, Habitual |
physiopathology |
Abortion, Spontaneous |
physiopathology |
Adult |
physiopathology |
Aged |
physiopathology |
Case-Control Studies |
physiopathology |
Datasets as Topic |
physiopathology |
European Continental Ancestry Group |
genetics |
Female |
genetics |
Gene Frequency |
genetics |
Genetic Predisposition to Disease |
genetics |
Genome-Wide Association Study |
genetics |
Humans |
genetics |
Inheritance Patterns |
genetics |
Medical History Taking |
genetics |
Middle Aged |
genetics |
Placenta |
physiopathology |
Polymorphism, Single Nucleotide |
physiopathology |
Pregnancy |
physiopathology |
Young Adult |
physiopathology |
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SUPPLEMENTARY MESH |
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GENE SYMBOLS |
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CHEMICALS |
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OTHER ID's |
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