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Nat Commun. 2019 Sep 2;10(1):3927. doi: 10.1038/s41467-019-11881-8.

Variants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration.

Author information

1
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
2
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark.
3
Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
4
Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
5
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
6
Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
7
Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
8
Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
9
Quantinuum Research, LLC, San Diego, CA, USA.
10
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
11
The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
12
Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
13
Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
14
ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain.
15
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
16
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
17
COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
18
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20520, Turku, Finland.
19
School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW, Australia.
20
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Gothenburg, Sweden.
21
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
22
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
23
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
24
Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
25
March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA.
26
Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
27
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
28
Statens Serum Institut, Center for Neonatal Screening, Department for Congenital Disorders, Copenhagen, Denmark.
29
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA.
30
Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY, 10029, USA.
31
NIHR Bristol Biomedical Research Centre, Bristol, UK.
32
Department of Surgery and Cancer, IRDB, Faculty of Medicine, Imperial College, London, W12 0NN, UK.
33
Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu, 200029 HUS, Finland.
34
Population, Policy and Practice, Great Ormond Street Institute for Child Health, University College London, London, UK.
35
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LJ, UK.
36
NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, OX3 7LJ, UK.
37
Center for Craniofacial and Dental Genetics, Department of Oral Biology School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
38
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
39
Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
40
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
41
Department of Anthropology, Northwestern University, Evanston, IL, USA.
42
Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
43
Division of Biostatistics, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
44
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
45
NIHR Exeter Clinical Research Facility, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital, Barrack Road, Exeter, EX2 5DW, UK.
46
Paavo Nurmi Centre, Sports & Exercise Medicine Unit, Department of Health and Physical Activity, University of Turku, 20520, Turku, Finland.
47
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, 20521, Turku, Finland.
48
K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
49
Department of Pediatrics, Haukeland University Hospital, Bergen, Norway.
50
Norwegian Institute of Public Health, Division of Health data and Digitalization, Department of Genetic Research and Bioinformatics, Oslo, Norway.
51
Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway.
52
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.
53
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
54
Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
55
National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
56
iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark.
57
Department of Biomedicine-Human Genetics, Aarhus University, Aarhus, Denmark.
58
Mental Health Center Copenhagen, Mental Health Services in the Capital Region of Denmark, Copenhagen, Denmark.
59
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
60
Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
61
Department of Epidemiology, University of Iowa, Iowa City, IA, USA.
62
Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland.
63
Department of Clinical Chemistry, Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, 33014, Tampere, Finland.
64
Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.
65
South Australian Health and Medical Research Institute, Adelaide, Australia.
66
Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
67
Institute of Health Sciences, University of Oulu, Oulu, Finland.
68
Department of Epidemiology and Biostatistics, School of Public Health, Medical Research Council-Health Protection Agency Centre for Environment and Health, Faculty of Medicine, Imperial College London, London, UK.
69
Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
70
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
71
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. fee@ssi.dk.

Abstract

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

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