Genetic effects on the timing of parturition and links to fetal birth weight,Nature Genetics

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Genetic effects on the timing of parturition and links to fetal birth weight
Nature Genetics ( IF 31.7 ) Pub Date : 2023-04-03 , DOI: 10.1038/s41588-023-01343-9
Pol Solé-Navais ₁ , Christopher Flatley ₁ , Valgerdur Steinthorsdottir ₂ , Marc Vaudel ₃ , Julius Juodakis ₁ , Jing Chen _{4,

5} , Triin Laisk ₆ , Abigail L LaBella ₇ , David Westergaard _{8,

9,

10} , Jonas Bacelis ₁ , Ben Brumpton ₁₁ , Line Skotte ₁₂ , Maria C Borges _{13,

14} , Øyvind Helgeland _{3,

15} , Anubha Mahajan _{16,

17} , Matthias Wielscher _{18,

19} , Frederick Lin ₂₀ , Catherine Briggs ₂₁ , Carol A Wang _{22,

23} , Gunn-Helen Moen _{11,

14,

24,

25} , Robin N Beaumont ₂₆ , Jonathan P Bradfield ₂₇ , Abin Abraham ₂₈ , Gudmar Thorleifsson ₂ , Maiken E Gabrielsen ₁₁ , Sisse R Ostrowski _{29,

30} , Dominika Modzelewska ₁ , Ellen A Nohr ₃₁ , Elina Hypponen _{32,

33} , Amit Srivastava _{5,

34} , Octavious Talbot ₂₀ , Catherine Allard ₃₅ , Scott M Williams ₃₆ , Ramkumar Menon ₃₇ , Beverley M Shields ₂₆ , Gardar Sveinbjornsson ₂ , Huan Xu _{5,

34} , Mads Melbye _{11,

30,

38,

39} , William Lowe ₂₀ , Luigi Bouchard _{40,

41} , Emily Oken ₂₁ , Ole B Pedersen _{30,

42} , Daniel F Gudbjartsson _{2,

43} , Christian Erikstrup _{44,

45} , Erik Sørensen ₂₉ , , , , Rolv T Lie _{38,

46} , Kari Teramo _{47,

48} , Mikko Hallman _{49,

50} , Thorhildur Juliusdottir ₂ , Hakon Hakonarson _{51,

52,

53,

54} , Henrik Ullum ₅₅ , Andrew T Hattersley ₂₆ , Line Sletner ₅₆ , Mario Merialdi ₅₇ , Sheryl L Rifas-Shiman ₂₁ , Thora Steingrimsdottir _{58,

59} , Denise Scholtens ₂₀ , Christine Power ₆₀ , Jane West ₆₁ , Mette Nyegaard ₆₂ , John A Capra ₆₃ , Anne H Skogholt ₁₁ , Per Magnus ₃₈ , Ole A Andreassen _{24,

64,

65} , Unnur Thorsteinsdottir _{2,

58} , Struan F A Grant _{52,

66,

67,

68} , Elisabeth Qvigstad _{24,

69} , Craig E Pennell _{22,

23} , Marie-France Hivert _{21,

70} , Geoffrey M Hayes ₂₀ , Marjo-Riitta Jarvelin _{18,

71,

72,

73} , Mark I McCarthy _{16,

17} , Deborah A Lawlor _{13,

14,

74} , Henriette S Nielsen _{9,

30,

75} , Reedik Mägi ₆ , Antonis Rokas _{7,

76,

77} , Kristian Hveem _{11,

78,

79} , Kari Stefansson _{2,

58} , Bjarke Feenstra ₁₂ , Pål Njolstad _{3,

80} , Louis J Muglia _{5,

34} , Rachel M Freathy _{13,

26} , Stefan Johansson _{3,

81} , Ge Zhang _{5,

34} , Bo Jacobsson _{1,

15}

Affiliation

Department of Obstetrics and Gynaecology, Sahlgrenska Academy, Institute of Clinical Science, University of Gothenburg, Gothenburg, Sweden.
deCODE genetics/Amgen, Reykjavik, Iceland.
Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway.
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.
Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.
Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.
Methods and Analysis, Statistics Denmark, Copenhagen, Denmark.
K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Genentech, South San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.
Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA.
School of Medicine and Public Health, College of Health, Medicine and Wellbeing, The University of Newcastle, Callaghan, New South Wales, Australia.
Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
University of Queensland Diamantina Institute, University of Queensland, Woolloongabba, Australia.
Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK.
Quantinuum Research LLC, Wayne, PA, USA.
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Clinical Immunology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
Research Unit of Gynecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
Australian Centre for Precision Health, Uni Clinical & Health Sciences, University of South Australia, Adelaide, Australia.
South Australian Health and Medical Research Institute, Adelaide, Australia.
Division of Human Genetics, Center for the Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Centre de recherche du Centre hospitalier universitaire de Sherbrooke (CHUS), Sherbrooke, Québec, Canada.
Department of Population and Quantitative Health Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Department of Obstetrics and Gynaecology, University of Texas Medical Branch, Galveston, TX, USA.
Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
Clinical Department of Laboratory Medicine, Centre intégré universitaire de santé et de services sociaux (CIUSSS) du Saguenay-Lac-St-Jean - Hôpital Universitaire de Chicoutimi, Saguenay, Québec, Canada.
Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark.
School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
Department of Clinical Medicine, Faculty of Health, University of Aarhus, Aarhus, Denmark.
Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland.
University of Helsinki, Helsinki, Finland.
PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland.
Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland.
The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
State Serum Institute, Copenhagen, Denmark.
Department of Pediatric and Adolescents Medicine, Akershus University Hospital, Lørenskog, Norway.
Maternal Newborn Health Innovations, PBC, Geneva, Switzerland.
Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Department of Obstetrics and Gynecology, Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland.
Population, Policy, Practice. Great Ormond Street Institute of Child Health, University College London, London, UK.
Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.
Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Bakar Computational Health Sciences Institute and Department of Epidemiology and Statistics, University of California San Francisco, San Francisco, CA, USA.
NORMENT Centre, University of Oslo, Oslo, Norway.
Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Center for Spatial and Functional Genomics Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Divisions of Human Genetics and Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Genetics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway.
Diabetes Unit, Massachusetts General Hospital, Boston, MA, USA.
Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
Biocenter of Oulu, University of Oulu, Linnanmaa, Oulu, Finland.
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
NIHR Bristol Biomedical Research Centre, Bristol, UK.
The Recurrent Pregnancy Loss Unit, The Capital Region, Copenhagen University Hospitals Rigshospitalet & Hvidovre Hospital, Hvidovre, Denmark.
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
HUNT Research Centre, Department of Public Health and Nursing, Norwegian University of Science and Technology, Levanger, Norway.
Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway.
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n = 195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n = 136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal–fetal relationship between gestational duration and birth weight.

中文翻译：

遗传对分娩时间的影响以及与胎儿出生体重的联系

分娩时间对于新生儿的生存和婴儿的健康至关重要。然而，其遗传基础在很大程度上仍未得到解决。我们提出了妊娠持续时间的母亲全基因组荟萃分析（ n = 195,555），确定了 22 个相关基因座（24 个独立变异）和分娩期间差异表达的基因的富集。对早产的荟萃分析（18,797 例，260,246 例对照）揭示了 6 个相关基因座以及与妊娠持续时间的巨大遗传相似性。对父母传播和非传播等位基因的分析 ( n = 136,833) 显示，15 个妊娠持续时间遗传变异通过母体基因组起作用，而 7 个同时通过母体和胎儿基因组起作用，2 个仅通过胎儿基因组起作用。最后，母体对妊娠持续时间的影响与胎儿对出生体重的影响表现出拮抗多效性的迹象：增加妊娠持续时间的母体等位基因对胎儿出生体重具有负面影响。本研究提供了关于遗传对分娩时间的影响以及妊娠持续时间和出生体重之间复杂的母婴关系的见解。

更新日期：2023-04-03

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