University of Oulu

Pasanen A, Karjalainen MK, FinnGen, Zhang G, Tiensuu H, Haapalainen AM, et al. (2023) Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci. PLoS Genet 19(10): e1010982.

Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci

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Author: Pasanen, Anu1; Karjalainen, Minna K.2; FinnGen;
Organizations: 1Research Unit of Clinical Medicine, Medical Research Center Oulu, University of Oulu, and Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
2Research Unit of Population Health, Faculty of Medicine, University of Oulu, Oulu, Finland
3Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Center for Prevention of Preterm Birth, Perinatal Institute and March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
4Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
5Department of Obstetrics and Gynaecology, Sahlgrenska Academy, Institute of Clinical Science, University of Gothenburg, Gothenburg, Sweden
6Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway
7Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
8Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America
9Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Analytic and Translational Genetics Unit, Department of Medicine, and the Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America
10Center for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
11Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland
12Burroughs Wellcome Fund, Research Triangle Park, Durham, North Carolina, United States of America
13Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
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Language: English
Published: Public Library of Science, 2023
Publish Date: 2023-11-06


Background: Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome.

Methods: We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,370 European mothers, respectively.

Results: The meta-analysis detected 15 loci associated with gestational duration, and four loci associated with preterm birth. Seven of the associated loci were novel. The loci mapped to several biologically plausible genes, for example HAND2 whose expression was previously shown to decrease during gestation, associated with gestational duration, and GC (Vitamin D-binding protein), associated with preterm birth. Downstream in silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action.

Conclusions: We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.

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Author summary

Annually, more than 15 million pregnancies are affected by preterm births all over the world. There are no effective ways to prevent preterm birth, and premature babies suffer from neonatal mortality and lifelong morbidities. Genetic factors of mother and fetus explain a large proportion, approximately 30–40%, of the of the variation in gestational age at delivery. To date, there have been just a few unbiased genome-wide investigations set out to locate these genes. Better characterization of the causal genetic mechanisms could suggest new strategies to treat and prevent preterm birth. In the current study, we aimed to identify maternal genetic factors that contribute to the timing of birth by meta-analyzing genome-wide association studies from European populations. We detected 17 independent loci that were associated with gestational duration and/or the risk of preterm birth. Ten of the loci replicated associations from previous studies, and seven were novel. The replicated associations provide strong evidence for the importance of these loci in the timing of birth, although the exact genes and causal variants and pathways still require further functional analysis. The seven novel associations provide further intriguing candidates that may account for the risk of preterm birth. Bioinformatics analysis proposed the associated loci have regulatory functions predominantly in immune cell types and reproductive tissues. The analysis further highlighted the unique nature or preterm birth as a phenotype, since the only traits with strong correlations were birth weight measures that are closely linked to the studied phenotypes. Our findings complement the knowledge of the genetic factors of preterm birth.

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Series: PLoS genetics
ISSN: 1553-7390
ISSN-E: 1553-7404
ISSN-L: 1553-7390
Volume: 19
Issue: 10
Article number: e1010982
DOI: 10.1371/journal.pgen.1010982
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
1184 Genetics, developmental biology, physiology
Funding: The FinnGen project is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie Inc., AstraZeneca UK Ltd, Biogen MA Inc., Bristol Myers Squibb (and Celgene Corporation & Celgene International II Sàrl), Genentech Inc., Merck Sharp & Dohme Corp, Pfizer Inc., GlaxoSmithKline Intellectual Property Development Ltd., Sanofi US Services Inc., Maze Therapeutics Inc., Janssen Biotech Inc, Novartis AG, and Boehringer Ingelheim. Research regarding spontaneous preterm birth performed at the University of Oulu was financed by the Jane and Aatos Erkko Foundation (MH, MR), Competitive State Research Financing of the Expert Responsibility Area of Oulu University Hospital (MR), Sigrid Jusélius Foundation (MH), Foundation for Pediatric Research (MR), Emil Aaltonen Foundation (AP), and Alma and K.A. Snellman Foundation (AP). BF received support from an Oak Foundation fellowship and a Novo Nordisk Foundation grant (12955). GZ is supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD101669, the Burroughs Wellcome Fund (Grant 10172896), the March of Dimes Prematurity Research Center Ohio Collaborative and the Bill & Melinda Gates Foundation. The Norwegian Mother and Child Cohort Study was supported by the Norwegian Ministry of Health and the Ministry of Education and Research, by the National Institute of Environmental Health Sciences (contract no. N01-ES-75558), the National Institute of Neurological Disorders and Stroke (UO1 NS 047537-01 and UO1 NS 047537-06A1), the Norwegian Research Council/FUGE (151918/S10, 183220/S10 and FRI-MEDBIO 249779). BJ was funded by the Swedish Research Council (2015-02559) and by from the Norwegian Research Council, a grant from the Jane and Dan Olsson Foundations, a grant (ALFGBG-426411) from the Swedish government to researchers in the public health service. The Danish National Birth Cohort was established with a significant grant from the Danish National Research Foundation. Additional support was obtained from the Danish Regional Committees, the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Health Foundation and other minor grants. The DNBC Biobank has been supported by the Novo Nordisk Foundation and the Lundbeck Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Dataset Reference: Summary statistics have been deposited in the GWAS Catalog ( with study accessions GCST90271752-GCST90271757. The data include meta-analysis summary statistics of the top 10,000 SNPs for gestational duration and preterm birth (GCST90271756 and GCST90271757), and summary statistics of the GWASs in Northern/Central Finnish cohort and in the FinnGen (GCST90271752-GCST90271755). The full GWAS summary statistics for the 23andMe discovery data set will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. Please visit for more information and to apply to access the data. For information regarding access to the most recent FinnGen data, please visit
Copyright information: © 2023 Pasanen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.