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The genetic architecture of sporadic and multiple consecutive miscarriage

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  • Triin Laisk, University of Tartu, Competence Centre on Health Technologies
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  • Ana Luiza G Soares, MRC Integrated Epidemiology Unit at the University of Bristol
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  • Teresa Ferreira, University of Oxford
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  • Jodie N Painter, QIMR Berghofer Medical Research Institute
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  • Jenny C Censin, University of Oxford
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  • Samantha Laber, University of Oxford
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  • Jonas Bacelis, Department of Obstetrics and Gynaecology, Sahlgrenska Academy, Sahlgrenska University Hospital/Östra, SE-416 85 Gothenburg
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  • Chia-Yen Chen, Broad Institute of Harvard and MIT
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  • Maarja Lepamets, University of Tartu
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  • Kuang Lin, University of Oxford
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  • Siyang Liu, Københavns Universitet
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  • Iona Y Millwood, University of Oxford
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  • Avinash Ramu, Department of Radiology, Washington University, St. Louis, MO; Department of Chemistry, Washington University, St. Louis, MO; Department of Medicine, Washington University, St. Louis, MO
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  • Jennifer Southcombe, University of Oxford
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  • Marianne S Andersen, Syddansk Universitet
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  • Ling Yang, University of Oxford
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  • Christian M Becker, University of Oxford
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  • Anders D Børglum
  • Scott D Gordon, QIMR Berghofer Medical Research Institute
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  • Jonas Bybjerg-Grauholm, iPSYCH -The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Statens Serum Institut
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  • Øyvind Helgeland, Norwegian Institute of Public Health, University of Bergen
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  • David M Hougaard, Statens Serum Institut, iPSYCH -The Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Xin Jin, South China University of Technology, Forensics Genomics International (FGI), BGI-Shenzhen, Shenzhen 518083, China.
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  • Stefan Johansson, University of Bergen, Haukeland University Hospital
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  • Julius Juodakis, Univ Gothenburg, University of Gothenburg, Gothenburg Global Biodivers Ctr
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  • Christiana Kartsonaki, University of Oxford
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  • Viktorija Kukushkina, University of Tartu
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  • Penelope A Lind, QIMR Berghofer Medical Research Institute
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  • Andres Metspalu, University of Tartu
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  • Grant W Montgomery, University of Queensland
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  • Andrew P Morris, University of Tartu, University of Oxford, University of Liverpool
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  • Ole Mors
  • Preben B Mortensen
  • Pål R Njølstad, University of Bergen, Haukeland University Hospital
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  • Merete Nordentoft, Københavns Universitet, iPSYCH -The Lundbeck Foundation Initiative for Integrative Psychiatric Research
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  • Dale R Nyholt, Queensland University of Technology
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  • Margaret Lippincott, Massachusetts General Hospital
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  • Stephanie Seminara, Massachusetts General Hospital
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  • Andres Salumets, University of Tartu, University of Helsinki
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  • Harold Snieder, University of Groningen
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  • Krina Zondervan, University of Oxford
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  • Thomas Werge, iPSYCH -The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Region Hovedstaden, Københavns Universitet
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  • Zhengming Chen, University of Oxford
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  • Donald F Conrad, Washington University
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  • Bo Jacobsson, Norwegian Institute of Public Health, University of Gothenburg
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  • Liming Li, Peking University Health Science Centre and Third Hospital
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  • Nicholas G Martin, QIMR Berghofer Medical Research Institute
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  • Benjamin M Neale, Broad Institute of Harvard and MIT, Massachusetts General Hospital
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  • Rasmus Nielsen, Københavns Universitet, University of California at Berkeley
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  • Robin G Walters, University of Oxford
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  • Ingrid Granne, University of Oxford
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  • Sarah E Medland, QIMR Berghofer Medical Research Institute
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  • Reedik Mägi, University of Tartu
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  • Deborah A Lawlor, MRC Integrated Epidemiology Unit at the University of Bristol, Bristol National Institute of Health Research Biomedical Research Centre, Bristol, United Kingdom.
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  • Cecilia M Lindgren, University of Oxford, Broad Institute

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 × 10-8, 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 × 10-8, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10-9, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10-8, 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.

OriginalsprogEngelsk
Artikelnummer5980
TidsskriftNature Communications
Vol/bind11
ISSN2041-1723
DOI
StatusUdgivet - nov. 2020

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