Abstract A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal ( n = 65,405), maternal ( n = 61,228) and paternal ( n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1 . Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth. Subject terms: Genetics research, Genetic association study
SHOW FULL ABSTRACT Robin N Beaumont, Christopher Flatley, Marc Vaudel, Xiaoping Wu, Jing Chen, Gunn-Helen Moen, Line Skotte, Øyvind Helgeland, Pol Solé-Navais, Karina Banasik, Clara Albiñana, Justiina Ronkainen, João Fadista, Sara Elizabeth Stinson, Katerina Trajanoska, Carol A Wang, David Westergaard, Sundararajan Srinivasan, Carlos Sánchez-Soriano, Jose Ramon Bilbao, Catherine Allard, Marika Groleau, Teemu Kuulasmaa, Daniel J Leirer, Frédérique White, Pierre-Étienne Jacques, Haoxiang Cheng, Ke Hao, Ole A Andreassen, Bjørn Olav Åsvold, Mustafa Atalay, Laxmi Bhatta, Luigi Bouchard, Ben Michael Brumpton, Søren Brunak, Jonas Bybjerg-Grauholm, Cathrine Ebbing, Paul Elliott, Line Engelbrechtsen, Christian Erikstrup, Marisa Estarlich, Stephen Franks, Romy Gaillard, Frank Geller, Jakob Grove, David M Hougaard, Eero Kajantie, Camilla S Morgen, Ellen A Nohr, Mette Nyegaard, Colin N A Palmer, Ole Birger Pedersen, Fernando Rivadeneira, Sylvain Sebert, Beverley M Shields, Camilla Stoltenberg, Ida Surakka, Lise Wegner Thørner, Henrik Ullum, Marja Vaarasmaki, Bjarni J Vilhjalmsson, Cristen J Willer, Timo A Lakka, Dorte Gybel-Brask, Mariona Bustamante, Torben Hansen, Ewan R Pearson, Rebecca M Reynolds, Sisse R Ostrowski, Craig E Pennell, Vincent W V Jaddoe, Janine F Felix, Andrew T Hattersley, Mads Melbye, Deborah A Lawlor, Kristian Hveem, Thomas Werge, Henriette Svarre Nielsen, Per Magnus, David M Evans, Bo Jacobsson, Marjo-Riitta Järvelin, Ge Zhang, Marie-France Hivert, Stefan Johansson, Rachel M Freathy, Bjarke Feenstra, Pål R Njølstad
1Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK 2Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden 3Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway 4Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway 5Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark 6Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA 7Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH USA 8Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway 9Frazer Institute, The University of Queensland, Brisbane, Queensland Australia 10K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway 11Population Health Science, Bristol Medical School, University of Bristol, Bristol, UK 12Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland Australia 13Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark 14National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark 15Research Unit of Population Health, University of Oulu, Oulu, Finland 16Department of Clinical Sciences, Lund University Diabetes Centre, Malmö, Sweden 17Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland 18Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 19Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 20Department of Human Genetics, McGill University, Montréal, Québec Canada 21School of Medicine and Public Health, College of Medicine, Public Health and Wellbeing, The University of Newcastle, Newcastle, New South Wales Australia 22Hunter Medical Research Institute, New Lambton Heights, Newcastle, New South Wales Australia 23Department of Obstetrics and Gynecology, Copenhagen University Hospital, Hvidovre, Denmark 24Methods and Analysis, Statistics Denmark, Copenhagen, Denmark 25Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK 26Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, UK 27Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain 28Biobizkaia Health Research Institute, Barakaldo, Spain 29Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders (CIBERDEM), Barcelona, Spain 30Centre de recherche du Centre Hospitalier de l’Universite de Sherbrooke, Sherbrooke, Québec Canada 31Département de Biologie, Faculté des Sciences, Université de Sherbrooke, Sherbrooke, Québec Canada 32Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio Campus, Kuopio, Finland 33Icahn School of Medicine at Mount Sinai, New York City, NY USA 34NORMENT Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway 35Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway 36HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway 37Department of Endocrinology, Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway 38Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec Canada 39Clinical 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 40Clinic of Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway 41Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark 42iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark 43Department of Clinical Science, University of Bergen, Bergen, Norway 44Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway 45Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK 46Department of Obstetrics and Gynecology, Herlev Hospital, Herlev, Denmark 47Department Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark 48Department Clinical Medicine, Aarhus University, Aarhus, Denmark 49Faculty of Nursing and Chiropody, Universitat de València, C/Menendez Pelayo, Valencia, Spain 50Epidemiology and Environmental Health Joint Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, FISABIO-Public Health, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain 51Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain 52Institute of Reproductive and Developmental Biology, Imperial College London, London, UK 53The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 54Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 55Department of Biomedicine—Human Genetics and the iSEQ Center, Aarhus University, Aarhus, Denmark 56Center for Genomics and Personalized Medicine, Aarhus, Denmark 57Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark 58Research Unit of Clinical Medicine, Medical Research Center, University of Oulu, Oulu, Finland 59Population Health Unit, Finnish Institute for Health and Welfare, Helsinki and Oulu, Oulu, Finland 60Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway 61National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 62Institute of Clinical research, University of Southern Denmark, Odense, Denmark 63Department of Health Science and Technology, Aalborg University, Aalborg, Denmark 64Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark 65Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark 66Norwegian Institute of Public Health, Oslo, Norway 67Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway 68Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI USA 69Department of Clinical Immunology, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark 70Statens Serum Institut, Copenhagen, Denmark 71Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulu, Finland 72Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI USA 73Department of Human Genetics, University of Michigan, Ann Arbor, MI USA 74Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland 75Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland 76Psychotherapeutic Outpatient Clinic, Mental Health Services, Capital Region, Copenhagen, Denmark 77ISGlobal, Institute for Global Health, Barcelona, Spain 78Universitat Pompeu Fabra (UPF), Barcelona, Spain 79Danish Cancer Institute, Copenhagen, Denmark 80Department of Genetics, Stanford University School of Medicine, Stanford, CA USA 81Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK 82Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Copenhagen, Denmark 83Lundbeck Center for Geogenetics, GLOBE Institute, University of Copenhagen, Copenhagen, Denmark 84Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway 85Center for Life Course Health Research, University of Oulu, Oulu, Finland 86MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK 87Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland 88Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA 89Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA 90March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH USA 91Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA USA 92Diabetes Unit, Massachusetts General Hospital, Boston, MA USA 93Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway 94Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway 