Nicole M. Warrington, Robin N. Beaumont, Momoko Horikoshi, Felix R. Day, Øyvind Helgeland, Charles Laurin, Jonas Bacelis, Shouneng Peng, Ke Hao, Bjarke Feenstra, Andrew R. Wood, Anubha Mahajan, Jessica Tyrrell, Neil R. Robertson, N. William Rayner, Zhen Qiao, Gunn-Helen Moen, Marc Vaudel, Carmen J. Marsit, Jia Chen, Michael Nodzenski, Theresia M. Schnurr, Mohammad H. Zafarmand, Jonathan P. Bradfield, Niels Grarup, Marjolein N. Kooijman, Ruifang Li-Gao, Frank Geller, Tarunveer S. Ahluwalia, Lavinia Paternoster, Rico Rueedi, Ville Huikari, Jouke-Jan Hottenga, Leo-Pekka Lyytikäinen, Alana Cavadino, Sarah Metrustry, Diana L. Cousminer, Ying Wu, Elisabeth Thiering, Carol A. Wang, Christian T. Have, Natalia Vilor-Tejedor, Peter K. Joshi, Jodie N. Painter, Ioanna Ntalla, Ronny Myhre, Niina Pitkänen, Elisabeth M. van Leeuwen, Raimo Joro, Vasiliki Lagou, Rebecca C. Richmond, Ana Espinosa, Sheila J. Barton, Hazel M. Inskip, John W. Holloway, Loreto Santa-Marina, Xavier Estivill, Wei Ang, Julie A. Marsh, Christoph Reichetzeder, Letizia Marullo, Berthold Hocher, Kathryn L. Lunetta, Joanne M. Murabito, Caroline L. Relton, Manolis Kogevinas, Leda Chatzi, Catherine Allard, Luigi Bouchard, Marie-France Hivert, Ge Zhang, Louis J. Muglia, Jani Heikkinen, Camilla S. Morgen, Antoine H. C. van Kampen, Barbera D. C. van Schaik, Frank D. Mentch, Claudia Langenberg, Jian’an Luan, Robert A. Scott, Jing Hua Zhao, Gibran Hemani, Susan M. Ring, Amanda J. Bennett, Kyle J. Gaulton, Juan Fernandez-Tajes, Natalie R. van Zuydam, Carolina Medina-Gomez, Hugoline G. de Haan, Frits R. Rosendaal, Zoltán Kutalik, Pedro Marques-Vidal, Shikta Das, Gonneke Willemsen, Hamdi Mbarek, Martina Müller-Nurasyid, Marie Standl, Emil V. R. Appel, Cilius E. Fonvig, Caecilie Trier, Catharina E. M. van Beijsterveldt, Mario Murcia, Mariona Bustamante, Sílvia Bonas-Guarch, David M. Hougaard, Josep M. Mercader, Allan Linneberg, Katharina E. Schraut, Penelope A. Lind, Sarah E. Medland, Beverley M. Shields, Bridget A. Knight, Jin-Fang Chai, Kalliope Panoutsopoulou, Meike Bartels, Friman Sánchez, Jakob Stokholm, David Torrents, Rebecca K. Vinding, Sara M. Willems, Mustafa Atalay, Bo L. Chawes, Peter Kovacs, Inga Prokopenko, Marcus A. Tuke, Hanieh Yaghootkar, Katherine S. Ruth, Samuel E. Jones, Po-Ru Loh, Anna Murray, Michael N. Weedon, Anke Tönjes, Michael Stumvoll, Kim F. Michaelsen, Aino-Maija Eloranta, Timo A. Lakka, Cornelia M. van Duijn, Wieland Kiess, Antje Körner, Harri Niinikoski, Katja Pahkala, Olli T. Raitakari, Bo Jacobsson, Eleftheria Zeggini, George V. Dedoussis, Yik-Ying Teo, Seang-Mei Saw, Grant W. Montgomery, Harry Campbell, James F. Wilson, Tanja G. M. Vrijkotte, Martine Vrijheid, Eco J. C. N. de Geus, M. Geoffrey Hayes, Haja N. Kadarmideen, Jens-Christian Holm, Lawrence J. Beilin, Craig E. Pennell, Joachim Heinrich, Linda S. Adair, Judith B. Borja, Karen L. Mohlke, Johan G. Eriksson, Elisabeth E. Widén, Andrew T. Hattersley, Tim D. Spector, Mika Kähönen, Jorma S. Viikari, Terho Lehtimäki, Dorret I. Boomsma, Sylvain Sebert, Peter Vollenweider, Thorkild I. A. Sørensen, Hans Bisgaard, Klaus Bønnelykke, Jeffrey C. Murray, Mads Melbye, Ellen A. Nohr, Dennis O. Mook-Kanamori, Fernando Rivadeneira, Albert Hofman, Janine F. Felix, Vincent W. V. Jaddoe, Torben Hansen, Charlotta Pisinger, Allan A. Vaag, Oluf Pedersen, André G. Uitterlinden, Marjo-Riitta Järvelin, Christine Power, Elina Hyppönen, Denise M. Scholtens, William L. Lowe, George Davey Smith, Nicholas J. Timpson, Andrew P. Morris, Nicholas J. Wareham, Hakon Hakonarson, Struan F. A. Grant, Timothy M. Frayling, Debbie A. Lawlor, Pål R. Njølstad, Stefan Johansson, Ken K. Ong, Mark I. McCarthy, John R. B. Perry, David M. Evans, Rachel M. Freathy
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight–blood pressure association is attributable to genetic effects, and not to intrauterine programming. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Royal Devon and Exeter Hospital, Exeter, United Kingdom; RIKEN Centre for Integrative Medical Sciences, Laboratory for Endocrinology, Metabolism and Kidney Diseases, Yokohama, Japan; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Pediatrics, Haukeland University Hospital, Bergen, Norway; Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom; Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark; European Centre for Environment and Human Health, University of Exeter, Truro, United Kingdom; Wellcome Sanger Institute, Hinxton, United Kingdom; Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States; Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States; Quantinuum Research, San Diego, CA, United States; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands; Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark; Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland; Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands; Amsterdam Public Health, Amsterdam, Netherlands; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland; Department of Clinical Chemistry, Finnish Cardiovascular Research Center–Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Section of Epidemiology and Biostatistics, School of Population Health, University of Auckland, Auckland, New Zealand; Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Department of Twin Research, King’s College London, St. Thomas’ Hospital, London, United Kingdom; Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Genetics, University of North Carolina, Chapel Hill, NC, United States; Institute of Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany; Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany; School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, NSW, Australia; Center for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain; Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom; QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, QLD, Australia; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom; Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland; Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; Department of Neuroscience, Katholieke Universiteit Leuven, Leuven, Belgium; VIB Center for Brain and Disease Research, Leuven, Belgium; ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; CIBER de Epidemiología y Salud Pública, Madrid, Spain; Hospital del Mar Medical Research Institute, Barcelona, Spain; Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Subdirección de Salud Pública y Adicciones de Gipuzkoa, San Sebastián, Spain; Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain; Sidra Medicine Research Department, Sidra Medicine, Doha, Qatar; Genomics Unit, Dexeus Woman’s Health, Barcelona, Spain; Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, WA, Australia; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany; Department of Life Sciences and Biotechnology, Genetic Section, University of Ferrara, Ferrara, Italy; Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China; Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States; Framingham Heart Study, Framingham, MA, United States; Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, United States; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, United States; Centre de recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, QC, Canada; Department of Biochemistry, Université de Sherbrooke, Sherbrooke, QC, Canada; Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, United States; Diabetes Center, Massachusetts General Hospital, Boston, MA, United States; Department of Medicine, Universite de Sherbrooke, Sherbooke, QC, Canada; Human Genetics Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States; Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States; March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, United States; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland; Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands; Department of Pediatrics, University of California San Diego, La Jolla, CA, United States; Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland; Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland; Medical Research Council Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Sciences, University College London, London, United Kingdom; Amsterdam Reproduction and Development, Amsterdam, Netherlands; Institute of Genetic Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany; Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany; Division of Genetic Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany; Children’s Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark; Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark; FISABIO–Universitat Jaume I–Universitat de València, Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain; Joint BSC–CGR–IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain; Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark; Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States; Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States; Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark; Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark; NIHR Exeter Clinical Research Facility, University of Exeter College of Medicine and Health and Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom; Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore; Computer Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain; IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany; Section of Genomics of Common Disease, Department of Medicine, Imperial College London, London, United Kingdom; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States; Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States; Medical Department, University of Leipzig, Leipzig, Germany; Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland; Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Pediatric Research Center, Department of Women’s andChild Health, University of Leipzig, Leipzig, Germany; Department of Pediatrics, Turku University Hospital, Turku, Finland; Department of Physiology, University of Turku, Turku, Finland; Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, University of Turku, Turku, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland; Institute of Translational Genomics, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany; Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece; Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore, Singapore; Singapore Eye Research Institute, Singapore, Singapore; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom; Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States; Quantitative and Systems Genomics Group, Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark; School of Medicine, Royal Perth Hospital, University of Western Australia, Perth, WA, Australia; Institute and Outpatient Clinic for Occupational Social and Environmental Medicine, Inner City Clinic, University Hospital Munich, Ludwig-Maximilians-University Munich, Munich, Germany; Department of Nutrition, University of North Carolina, Chapel Hill, NC, United States; USC-Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines; Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines; National Institute for Health and Welfare, Helsinki, Finland; Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland; Department of Clinical Physiology, Finnish Cardiovascular Research Center–Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Division of Medicine, Turku University Hospital, Turku, Finland; Department of Medicine, University of Turku, Turku, Finland; Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom; Biocenter Oulu, University of Oulu, Oulu, Finland; Department of Genomics of Complex Diseases, Imperial College London, London, United Kingdom; Department of Pediatrics, University of Iowa, Iowa City, IA, United States; Department of Medicine, Stanford School of Medicine, Stanford, CA, United States; Research Unit for Gynaecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, Netherlands; Research Center for Prevention and Health, Center for Sundhed, Rigshospitalet Glostrup, Copenhagen University, Glostrup, Denmark; Cardiovascular, Renal and Metabolism, Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden; Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland; Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, United Kingdom; Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia; NIHR Bristol Biomedical Research Centre, Bristol, United Kingdom; Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom; Estonian Genome Center, University of Tartu, Tartu, Estonia; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway; Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom; NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
