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.

Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.

Details

Title
The genetic architecture of sporadic and multiple consecutive miscarriage
Author
Laisk Triin 1   VIAFID ORCID Logo  ; Soares, Ana Luiza, G 2   VIAFID ORCID Logo  ; Ferreira, Teresa 3 ; Painter, Jodie N 4   VIAFID ORCID Logo  ; Censin, Jenny C 5   VIAFID ORCID Logo  ; Laber Samantha 5 ; Bacelis Jonas 6   VIAFID ORCID Logo  ; Chia-Yen, Chen 7 ; Maarja, Lepamets 8 ; Lin, Kuang 9 ; Liu Siyang 10 ; Millwood, Iona Y 11 ; Ramu Avinash 12 ; Southcombe, Jennifer 13 ; Andersen, Marianne S 14 ; Yang, Ling 11 ; Becker, Christian M 13   VIAFID ORCID Logo  ; Børglum, Anders D 15   VIAFID ORCID Logo  ; Gordon, Scott D 4   VIAFID ORCID Logo  ; Jonas, Bybjerg-Grauholm 16   VIAFID ORCID Logo  ; Helgeland Øyvind 17 ; Hougaard, David M 16   VIAFID ORCID Logo  ; Jin, Xin 18 ; Johansson, Stefan 19   VIAFID ORCID Logo  ; Juodakis Julius 20   VIAFID ORCID Logo  ; Kartsonaki Christiana 11 ; Kukushkina Viktorija 8 ; Lind, Penelope A 4   VIAFID ORCID Logo  ; Metspalu Andres 21   VIAFID ORCID Logo  ; Montgomery, Grant W 22   VIAFID ORCID Logo  ; Morris, Andrew P 23   VIAFID ORCID Logo  ; Mors Ole 24 ; Mortensen, Preben B 25 ; Njølstad, Pål R 26   VIAFID ORCID Logo  ; Nordentoft Merete 27 ; Nyholt Dale R 28   VIAFID ORCID Logo  ; Lippincott, Margaret 29 ; Seminara, Stephanie 29 ; Salumets Andres 30 ; Snieder Harold 31   VIAFID ORCID Logo  ; Zondervan Krina 32   VIAFID ORCID Logo  ; Werge, Thomas 33   VIAFID ORCID Logo  ; Chen, Zhengming 9   VIAFID ORCID Logo  ; Conrad, Donald F 12 ; Jacobsson, Bo 34   VIAFID ORCID Logo  ; Li, Liming 35   VIAFID ORCID Logo  ; Martin, Nicholas G 4   VIAFID ORCID Logo  ; Neale, Benjamin M 7   VIAFID ORCID Logo  ; Nielsen, Rasmus 36   VIAFID ORCID Logo  ; Walters, Robin G 11   VIAFID ORCID Logo  ; Granne Ingrid 13 ; Medland, Sarah E 4   VIAFID ORCID Logo  ; Reedik, Mägi 21 ; Lawlor, Deborah A 37   VIAFID ORCID Logo  ; Lindgren, Cecilia M 38   VIAFID ORCID Logo 

1  University of Tartu, Department of Obstetrics and Gynecology, Institute of Clinical Medicine, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661); University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661); Competence Centre on Health Technologies, Tartu, Estonia (GRID:grid.487355.8) 
2  MRC Integrated Epidemiology Unit at the University of Bristol, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); University of Bristol, Population Health Sciences, Bristol Medical School, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
3  Oxford University, Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
4  QIMR Berghofer Medical Research Institute, Herston, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
5  Oxford University, Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, Wellcome Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
6  Sahlgrenska University Hospital Östra, Department of Obstetrics and Gynecology, Gothenburg, Sweden (GRID:grid.1649.a) (ISNI:000000009445082X) 
7  Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Massachusetts General Hospital, Psychiatric and Neurodevelopmental Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) 
8  University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661); University of Tartu, Institute of Molecular and Cell Biology, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
9  University of Oxford, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
10  BGI-Shenzhen, Shenzhen, Guangdong, China (GRID:grid.21155.32) (ISNI:0000 0001 2034 1839); University of Copenhagen, Bioinformatics Centre, Department of Biology, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
11  University of Oxford, Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, Medical Research Council Population Health Research Unit (PHRU), Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
12  Washington University in St. Louis, Department of Genetics, Saint Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
13  University of Oxford, Nuffield Department of Women’s and Reproductive Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
14  Odense University Hospital, Department of Endocrinology, Odense, Denmark (GRID:grid.7143.1) (ISNI:0000 0004 0512 5013) 
15  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Aarhus University, Department of Biomedicine and Center for Integrative Sequencing, iSEQ, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722); Aarhus University and University Hospital, Center for Genomics and Personalized Medicine, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
16  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Statens Serum Institut, Department for Congenital Disorders, Copenhagen, Denmark (GRID:grid.6203.7) (ISNI:0000 0004 0417 4147) 
17  Norwegian Institute of Public Health, Department of Genetics and Bioinformatics, Health Data and Digitalisation, Oslo, Norway (GRID:grid.418193.6) (ISNI:0000 0001 1541 4204); University of Bergen, KG Jebsen Center for Diabetes Research, Department of Clinical Science, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443) 
18  BGI-Shenzhen, Shenzhen, Guangdong, China (GRID:grid.21155.32) (ISNI:0000 0001 2034 1839); South China University of Technology, Guangzhou, School of Medicine, Guangdong, China (GRID:grid.79703.3a) (ISNI:0000 0004 1764 3838) 
19  University of Bergen, KG Jebsen Center for Diabetes Research, Department of Clinical Science, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443); Haukeland University Hospital, Department of Medical Genetics, Bergen, Norway (GRID:grid.412008.f) (ISNI:0000 0000 9753 1393) 
20  University of Gothenburg, Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden (GRID:grid.8761.8) (ISNI:0000 0000 9919 9582) 
21  University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661) 
22  University of Queensland, St Lucia, Australia (GRID:grid.1003.2) (ISNI:0000 0000 9320 7537) 
23  University of Tartu, Estonian Genome Center, Institute of Genomics, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661); University of Oxford, Wellcome Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Liverpool, Department of Biostatistics, Liverpool, UK (GRID:grid.10025.36) (ISNI:0000 0004 1936 8470) 
24  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Aarhus University Hospital – Psychiatry, Psychosis Research Unit, Aarhus, Denmark (GRID:grid.154185.c) (ISNI:0000 0004 0512 597X) 
25  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Aarhus University, National Centre for Register-Based Research, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
26  University of Bergen, KG Jebsen Center for Diabetes Research, Department of Clinical Science, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443); Haukeland University Hospital, Department of Pediatrics, Bergen, Norway (GRID:grid.412008.f) (ISNI:0000 0000 9753 1393) 
27  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Mental Health Services in the Capital Region of Denmark, Copenhagen University Hospital, Mental Health Center Copenhagen, Copenhagen, Denmark (GRID:grid.466916.a) (ISNI:0000 0004 0631 4836) 
28  Queensland University of Technology, School of Biomedical Sciences, Faculty of Health, Brisbane, Australia (GRID:grid.1024.7) (ISNI:0000000089150953) 
29  Massachusetts General Hospital, Reproductive Endocrine Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
30  University of Tartu, Department of Obstetrics and Gynecology, Institute of Clinical Medicine, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661); Competence Centre on Health Technologies, Tartu, Estonia (GRID:grid.487355.8); University of Tartu, Institute of Bio- and Translational Medicine, Tartu, Estonia (GRID:grid.10939.32) (ISNI:0000 0001 0943 7661); University of Helsinki and Helsinki University Hospital, Department of Obstetrics and Gynecology, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
31  University Medical Center Groningen, Department of Epidemiology, University of Groningen, Groningen, the Netherlands (GRID:grid.4494.d) (ISNI:0000 0000 9558 4598) 
32  University of Oxford, Wellcome Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, Nuffield Department of Women’s and Reproductive Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
33  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Mental Health Services Copenhagen, Institute of Biological Psychiatry, MHC Sct. Hans, Roskilde, Denmark (GRID:grid.466916.a) (ISNI:0000 0004 0631 4836); University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
34  Sahlgrenska University Hospital Östra, Department of Obstetrics and Gynecology, Gothenburg, Sweden (GRID:grid.1649.a) (ISNI:000000009445082X); Norwegian Institute of Public Health, Department of Genetics and Bioinformatics, Health Data and Digitalisation, Oslo, Norway (GRID:grid.418193.6) (ISNI:0000 0001 1541 4204) 
35  Peking University, Department of Epidemiology & Biostatistics, Peking University Health Science Centre, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319) 
36  University of California Berkeley, Department of Integrative Biology, Berkeley, USA (GRID:grid.47840.3f) (ISNI:0000 0001 2181 7878); University of Copenhagen, Centre for GeoGenetics, Natural History Museum of Denmark, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
37  MRC Integrated Epidemiology Unit at the University of Bristol, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); University of Bristol, Population Health Sciences, Bristol Medical School, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); Bristol National Institute of Health Research Biomedical Research Centre, Bristol, UK (GRID:grid.5337.2) 
38  Oxford University, Big Data Institute, Li Ka Shing Center for Health for Health Information and Discovery, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, Wellcome Centre for Human Genetics, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); Broad Institute, Program in Medical and Population Genetics, Boston, USA (GRID:grid.66859.34) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-19742-5
ProQuest document ID
2473251377
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.