The genetic architecture of sporadic and multiple consecutive miscarriage

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, Avinash Ramu, Jennifer Southcombe, Marianne S. Andersen, Ling Yang, Christian M. Becker, Anders D. Børglum, Scott D. Gordon, Jonas Bybjerg-Grauholm, Øyvind Helgeland, David M. Hougaard, Xin Jin, Stefan Johansson, Julius Juodakis, Christiana Kartsonaki, Viktorija Kukushkina, Penelope A. Lind, Andres Metspalu, Grant W. Montgomery, Andrew P. Morris, Ole Mors, Preben B. Mortensen, Pål R. Njølstad, Merete Nordentoft, Dale R. Nyholt, Margaret Lippincott, Stephanie Seminara, Andres Salumets, Harold Snieder, Krina Zondervan, Thomas Werge, Zhengming Chen, Donald F. Conrad, Bo Jacobsson, Liming Li, Nicholas G. Martin, Benjamin M. Neale, Rasmus Nielsen, Robin G. Walters, Ingrid Granne, Sarah E. Medland, Reedik Mägi, Deborah A. Lawlor and Cecilia M. Lindgren ()
Additional contact information
Triin Laisk: University of Tartu
Ana Luiza G. Soares: MRC Integrated Epidemiology Unit at the University of Bristol
Teresa Ferreira: Oxford University
Jodie N. Painter: QIMR Berghofer Medical Research Institute
Jenny C. Censin: Oxford University
Samantha Laber: Oxford University
Jonas Bacelis: Sahlgrenska University Hospital Östra
Chia-Yen Chen: Massachusetts General Hospital
Maarja Lepamets: University of Tartu
Kuang Lin: University of Oxford
Siyang Liu: BGI-Shenzhen, Shenzhen
Iona Y. Millwood: 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
Christian M. Becker: University of Oxford
Anders D. Børglum: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Scott D. Gordon: QIMR Berghofer Medical Research Institute
Jonas Bybjerg-Grauholm: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Øyvind Helgeland: Norwegian Institute of Public Health
David M. Hougaard: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Xin Jin: BGI-Shenzhen, Shenzhen
Stefan Johansson: University of Bergen
Julius Juodakis: University of Gothenburg
Christiana Kartsonaki: University of Oxford
Viktorija Kukushkina: 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
Ole Mors: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Preben B. Mortensen: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Pål R. Njølstad: University of Bergen
Merete Nordentoft: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Dale R. Nyholt: Queensland University of Technology
Margaret Lippincott: Massachusetts General Hospital
Stephanie Seminara: Massachusetts General Hospital
Andres Salumets: University of Tartu
Harold Snieder: University Medical Center Groningen
Krina Zondervan: University of Oxford
Thomas Werge: The Lundbeck Foundation Initiative for Integrative Psychiatric Research
Zhengming Chen: University of Oxford
Donald F. Conrad: Washington University in St. Louis
Bo Jacobsson: Sahlgrenska University Hospital Östra
Liming Li: Peking University
Nicholas G. Martin: QIMR Berghofer Medical Research Institute
Benjamin M. Neale: Massachusetts General Hospital
Rasmus Nielsen: University of California Berkeley
Robin G. Walters: 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
Cecilia M. Lindgren: Oxford University

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19742-5

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