Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
33239672
TITLE
The genetic architecture of sporadic and multiple consecutive miscarriage.
ABSTRACT
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.
DATE PUBLISHED
2020 11 25
HISTORY
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
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Laisk T Laisk Triin T Competence Centre on Health Technologies, Tartu, Estonia. triin.laisk@ut.ee.
Soares ALG Soares Ana Luiza G ALG Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Ferreira T Ferreira Teresa T Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford University, Oxford, UK.
Painter JN Painter Jodie N JN QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Censin JC Censin Jenny C JC Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Laber S Laber Samantha S Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
Bacelis J Bacelis Jonas J Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden.
Chen CY Chen Chia-Yen CY Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Lepamets M Lepamets Maarja M Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Lin K Lin Kuang K Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Liu S Liu Siyang S Bioinformatics Centre, Department of Biology, University of Copenhagen, 2200, Copenhagen, Denmark.
Millwood IY Millwood Iona Y IY Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK.
Ramu A Ramu Avinash A Department of Genetics, Washington University in St. Louis, Saint Louis, MO, USA.
Southcombe J Southcombe Jennifer J Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
Andersen MS Andersen Marianne S MS Department of Endocrinology, Odense University Hospital, Odense, Denmark.
Yang L Yang Ling L Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK.
Becker CM Becker Christian M CM Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
Børglum AD Børglum Anders D AD Center for Genomics and Personalized Medicine, Aarhus University and University Hospital, Aarhus, Denmark.
Gordon SD Gordon Scott D SD QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Bybjerg-Grauholm J Bybjerg-Grauholm Jonas J Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Helgeland Ø Helgeland Øyvind KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.
Hougaard DM Hougaard David M DM Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
Jin X Jin Xin X School of Medicine, South China University of Technology, Guangzhou, 510006, Guangdong, China.
Johansson S Johansson Stefan S Department of Medical Genetics, Haukeland University Hospital, N-5021, Bergen, Norway.
Juodakis J Juodakis Julius J Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Kartsonaki C Kartsonaki Christiana C Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK.
Kukushkina V Kukushkina Viktorija V Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
Lind PA Lind Penelope A PA QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Metspalu A Metspalu Andres A Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Montgomery GW Montgomery Grant W GW University of Queensland, St Lucia, QLD, Australia.
Morris AP Morris Andrew P AP Department of Biostatistics, University of Liverpool, Liverpool, UK.
Mors O Mors Ole O Psychosis Research Unit, Aarhus University Hospital - Psychiatry, Aarhus, Denmark.
Mortensen PB Mortensen Preben B PB National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
Njølstad PR Njølstad Pål R PR Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
Nordentoft M Nordentoft Merete M Copenhagen University Hospital, Mental Health Center Copenhagen, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark.
Nyholt DR Nyholt Dale R DR School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
Lippincott M Lippincott Margaret M Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
Seminara S Seminara Stephanie S Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA.
Salumets A Salumets Andres A Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
Snieder H Snieder Harold H Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Zondervan K Zondervan Krina K Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
Werge T Werge Thomas T Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Chen Z Chen Zhengming Z Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Conrad DF Conrad Donald F DF Department of Genetics, Washington University in St. Louis, Saint Louis, MO, USA.
Jacobsson B Jacobsson Bo B Department of Genetics and Bioinformatics, Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway.
Li L Li Liming L Department of Epidemiology & Biostatistics, Peking University Health Science Centre, Peking University, Beijing, China.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Neale BM Neale Benjamin M BM Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nielsen R Nielsen Rasmus R Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Copenhagen, Denmark.
Walters RG Walters Robin G RG Medical Research Council Population Health Research Unit (PHRU), University of Oxford, Oxford, UK.
Granne I Granne Ingrid I Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK.
Medland SE Medland Sarah E SE QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
Mägi R Mägi Reedik R Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
Lawlor DA Lawlor Deborah A DA Bristol National Institute of Health Research Biomedical Research Centre, Bristol, UK.
Lindgren CM Lindgren Cecilia M CM Program in Medical and Population Genetics, Broad Institute, Boston, MA, USA. cecilia.lindgren@bdi.ox.ac.uk.
INVESTIGATORS
JOURNAL
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
MEDLINE JOURNAL
MEDLINETA: Nat Commun
COUNTRY: England
ISSNLINKING: 2041-1723
NLMUNIQUEID: 101528555
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
GRANTS
GRANTID AGENCY COUNTRY
HHSN268201600001C NHLBI NIH HHS United States
N01ES75558 NIEHS NIH HHS United States
British Heart Foundation United Kingdom
WT088806 Wellcome Trust United Kingdom
MC-PC-13049 Medical Research Council United Kingdom
U01 HG005152 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
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
HHSN268201600018C NHLBI NIH HHS United States
U01 HG004424 NHGRI NIH HHS United States
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
GENERAL NOTE
KEYWORDS
MESH HEADINGS
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
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's