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The genetic architecture of sporadic and multiple consecutive miscarriage

Author

Listed:
  • Triin Laisk

    (University of Tartu
    University of Tartu
    Competence Centre on Health Technologies)

  • Ana Luiza G. Soares

    (MRC Integrated Epidemiology Unit at the University of Bristol
    University of Bristol)

  • Teresa Ferreira

    (Oxford University)

  • Jodie N. Painter

    (QIMR Berghofer Medical Research Institute)

  • Jenny C. Censin

    (Oxford University
    University of Oxford)

  • Samantha Laber

    (Oxford University
    University of Oxford)

  • Jonas Bacelis

    (Sahlgrenska University Hospital Östra)

  • Chia-Yen Chen

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Maarja Lepamets

    (University of Tartu
    University of Tartu)

  • Kuang Lin

    (University of Oxford)

  • Siyang Liu

    (BGI-Shenzhen, Shenzhen
    University of Copenhagen)

  • Iona Y. Millwood

    (University of Oxford
    University of Oxford)

  • Avinash Ramu

    (Washington University in St. Louis)

  • Jennifer Southcombe

    (University of Oxford)

  • Marianne S. Andersen

    (Odense University Hospital)

  • Ling Yang

    (University of Oxford
    University of Oxford)

  • Christian M. Becker

    (University of Oxford)

  • Anders D. Børglum

    (The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Aarhus University
    Aarhus University and University Hospital)

  • Scott D. Gordon

    (QIMR Berghofer Medical Research Institute)

  • Jonas Bybjerg-Grauholm

    (The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Statens Serum Institut)

  • Øyvind Helgeland

    (Norwegian Institute of Public Health
    University of Bergen)

  • David M. Hougaard

    (The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Statens Serum Institut)

  • Xin Jin

    (BGI-Shenzhen, Shenzhen
    South China University of Technology, Guangzhou)

  • Stefan Johansson

    (University of Bergen
    Haukeland University Hospital)

  • Julius Juodakis

    (University of Gothenburg)

  • Christiana Kartsonaki

    (University of Oxford
    University of Oxford)

  • Viktorija Kukushkina

    (University of Tartu
    University of Tartu)

  • Penelope A. Lind

    (QIMR Berghofer Medical Research Institute)

  • Andres Metspalu

    (University of Tartu)

  • Grant W. Montgomery

    (University of Queensland)

  • Andrew P. Morris

    (University of Tartu
    University of Oxford
    University of Liverpool)

  • Ole Mors

    (The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Aarhus University Hospital – Psychiatry)

  • Preben B. Mortensen

    (The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Aarhus University)

  • Pål R. Njølstad

    (University of Bergen
    Haukeland University Hospital)

  • Merete Nordentoft

    (The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Mental Health Services in the Capital Region of Denmark)

  • Dale R. Nyholt

    (Queensland University of Technology)

  • Margaret Lippincott

    (Massachusetts General Hospital)

  • Stephanie Seminara

    (Massachusetts General Hospital)

  • Andres Salumets

    (University of Tartu
    Competence Centre on Health Technologies
    University of Tartu
    University of Helsinki and Helsinki University Hospital)

  • Harold Snieder

    (University Medical Center Groningen)

  • Krina Zondervan

    (University of Oxford
    University of Oxford)

  • Thomas Werge

    (The Lundbeck Foundation Initiative for Integrative Psychiatric Research
    Mental Health Services Copenhagen
    University of Copenhagen)

  • Zhengming Chen

    (University of Oxford)

  • Donald F. Conrad

    (Washington University in St. Louis)

  • Bo Jacobsson

    (Sahlgrenska University Hospital Östra
    Norwegian Institute of Public Health)

  • Liming Li

    (Peking University)

  • Nicholas G. Martin

    (QIMR Berghofer Medical Research Institute)

  • Benjamin M. Neale

    (Massachusetts General Hospital
    Massachusetts General Hospital
    Broad Institute of MIT and Harvard)

  • Rasmus Nielsen

    (University of California Berkeley
    University of Copenhagen)

  • Robin G. Walters

    (University of Oxford
    University of Oxford)

  • Ingrid Granne

    (University of Oxford)

  • Sarah E. Medland

    (QIMR Berghofer Medical Research Institute)

  • Reedik Mägi

    (University of Tartu)

  • Deborah A. Lawlor

    (MRC Integrated Epidemiology Unit at the University of Bristol
    University of Bristol
    Bristol National Institute of Health Research Biomedical Research Centre)

  • Cecilia M. Lindgren

    (Oxford University
    University of Oxford
    Broad Institute)

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 × 10−8, 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.

Suggested Citation

  • Triin Laisk & Ana Luiza G. Soares & Teresa Ferreira & Jodie N. Painter & Jenny C. Censin & Samantha Laber & Jonas Bacelis & Chia-Yen Chen & Maarja Lepamets & Kuang Lin & Siyang Liu & Iona Y. Millwood , 2020. "The genetic architecture of sporadic and multiple consecutive miscarriage," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19742-5
    DOI: 10.1038/s41467-020-19742-5
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    Cited by:

    1. Gudny A. Arnadottir & Asmundur Oddsson & Brynjar O. Jensson & Svanborg Gisladottir & Mariella T. Simon & Asgeir O. Arnthorsson & Hildigunnur Katrinardottir & Run Fridriksdottir & Erna V. Ivarsdottir &, 2022. "Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    2. Kyuto Sonehara & Yoshitaka Yano & Tatsuhiko Naito & Shinobu Goto & Hiroyuki Yoshihara & Takahiro Otani & Fumiko Ozawa & Tamao Kitaori & Koichi Matsuda & Takashi Nishiyama & Yukinori Okada & Mayumi Sug, 2024. "Common and rare genetic variants predisposing females to unexplained recurrent pregnancy loss," Nature Communications, Nature, vol. 15(1), pages 1-9, December.

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