Momoko Horikoshi, Robin N. Beaumont, Felix R. Day, Nicole M. Warrington, Marjolein N. Kooijman, Juan Fernandez-Tajes, Bjarke Feenstra, Natalie R. Van Zuydam, Kyle J. Gaulton, Niels Grarup, Jonathan P. Bradfield, David P. Strachan, Ruifang Li-Gao, Tarunveer S. Ahluwalia, Eskil Kreiner, Rico Rueedi, Leo-Pekka Lyytikaïnen, Diana L. Cousminer, Ying Wu, Elisabeth Thiering, Carol A. Wang, Christian T. Have, Jouke-Jan Hottenga, Natalia Vilor-Tejedor, Peter K. Joshi, Eileen Tai Hui Boh, Ioanna Ntalla, Niina Pitkänen, Anubha Mahajan, Elisabeth M. Van Leeuwen, Raimo Joro, Vasiliki Lagou, Michael Nodzenski, Louise A. Diver, Krina T. Zondervan, Mariona Bustamante, Pedro Marques-Vidal, Josep M. Mercader, Amanda J. Bennett, Nilufer Rahmioglu, Dale R. Nyholt, Ronald C. W. Ma, Claudia H. T. Tam, Wing Hung Tam, Santhi K. Ganesh, Frank J. A. Van Rooij, Samuel E. Jones, Po-Ru Loh, Katherine S. Ruth, Marcus A. Tuke, Jessica Tyrrell, Andrew R. Wood, Hanieh Yaghootkar, Denise M. Scholtens, Lavinia Paternoster, Inga Prokopenko, Peter Kovacs, Mustafa Atalay, Sara M. Willems, Kalliope Panoutsopoulou, Xu Wang, Lisbeth Carstensen, Frank Geller, Katharina E. Schraut, Mario Murcia, Catharina E. M. Van Beijsterveldt, Gonneke Willemsen, Emil V. R. Appel, Cilius E. Fonvig, Caecilie Trier, Carla M. T. Tiesler, Marie Standl, Zoltán Kutalik, Sílvia Bonàs-Guarch, David M. Hougaard, Friman Sánchez, David Torrents, Johannes Waage, Mads V. Hollegaard, Hugoline G. De Haan, Frits R. Rosendaal, Carolina Medina-Gomez, Susan M. Ring, Gibran Hemani, George McMahon, Neil R. Robertson, Christopher J. Groves, Claudia Langenberg, Jian'An Luan, Robert A. Scott, Jing Hua Zhao, Frank D. Mentch, Scott M. MacKenzie, Rebecca M. Reynolds, William L. Lowe, Anke Tönjes, Michael Stumvoll, Virpi Lindi, Timo A. Lakka, Cornelia M. Van Duijn, Wieland Kiess, Antje Körner, Thorkild I. A. Sørensen, Harri Niinikoski, Katja Pahkala, Olli T. Raitakari, Eleftheria Zeggini, George V. Dedoussis, Yik-Ying Teo, Seang-Mei Saw, Mads Melbye, Harry Campbell, James F. Wilson, Martine Vrijheid, Eco J. C. N. De Geus, Dorret I. Boomsma, Haja N. Kadarmideen, Jens-Christian Holm, Torben Hansen, Sylvain Sebert, Andrew T. Hattersley, Lawrence J. Beilin, John P. Newnham, Craig E. Pennell, Joachim Heinrich, Linda S. Adair, Judith B. Borja, Karen L. Mohlke, Johan G. Eriksson, Elisabeth Widén, Mika Kähönen, Jorma S. Viikari, Terho Lehtimäki, Peter Vollenweider, Klaus Bønnelykke, Hans Bisgaard, Dennis O. Mook-Kanamori, Albert Hofman, Fernando Rivadeneira, André G. Uitterlinden, Charlotta Pisinger, Oluf Pedersen, Christine Power, Elina Hyppönen, Nicholas J. Wareham, Hakon Hakonarson, Eleanor Davies, Brian R. Walker, Vincent W. V. Jaddoe, Marjo-Riitta Järvelin, Struan F. A. Grant, Allan A. Vaag, Debbie A. Lawlor, Timothy M. Frayling, George Davey Smith, Andrew P. Morris, Ken K. Ong, Janine F. Felix, Nicholas J. Timpson, John R. B. Perry, David M. Evans, Mark I. McCarthy, Rachel M. Freathy
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10-8). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (Rg =-0.22, P = 5.5 × 10-13), T2D (Rg =-0.27, P = 1.1 × 10-6) and coronary artery disease (Rg =-0.30, P = 6.5 × 10-9). In addition, using large-cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10-4). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated. © 2016 Macmillan Publishers Limited, part of Springer Nature.
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX37BN, United Kingdom; Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, OX37LE, United Kingdom; Institute of Biomedical and Clinical Science, University of Exeter, University of Exeter, Exeter, EX25DW, United Kingdom; MRC Epidemiology Unit, University of Cambridge, School of Clinical Medicine, Cambridge, CB20QQ, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, 4102, QLD, Australia; School of Women's and Infants' Health, University of Western Australia, Perth, 6009, WA, Australia; Generation R Study Group, University Medical Center Rotterdam, Rotterdam, 3015, Netherlands; Department of Epidemiology, University Medical Center Rotterdam, Rotterdam, 3015, Netherlands; Department of Pediatrics, University Medical Center Rotterdam, Rotterdam, 3015, Netherlands; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, DK-2300, Denmark; Department of Pediatrics, University of California San Diego, San Diego, 92093, CA, United States; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, 19104, PA, United States; Population Health Research Institute, St George's University of London, Cranmer Terrace, London, SW170RE, United Kingdom; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, 2333, Netherlands; Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, 2820, Denmark; Steno Diabetes Center, Gentofte, DK-2820, Denmark; Department of Computational Biology, University of Lausanne, Lausanne, 1011, Switzerland; Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland; Department of Clinical Chemistry, Fimlab Laboratories, Tampere, 33520, Finland; Department of Clinical Chemistry, University of Tampere, School of Medicine, Tampere, 33014, Finland; Institute for Molecular Medicine, University of Helsinki, Helsinki, FI-00100, Finland; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, 19104, PA, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, United States; Department of Genetics, University of North Carolina, Chapel Hill, 27599, NC, United States; Institute of Epidemiology i, German Research Center for Environmental Health, Neuherberg, 85764, Germany; Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children's Hospital, University of Munich, Munich, 80337, Germany; Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit, Amsterdam, 1081, Netherlands; Centre for Research in Environmental Epidemiology, Barcelona, 08003, Spain; Universitat Pompeu Fabra, Barcelona, 08002, Spain; CIBER de Epidemiologiá y Salud Pública, Madrid, 28029, Spain; Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, EH89AG, United Kingdom; Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, 119077, Singapore; William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M6BQ, United Kingdom; Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, 17671, Greece; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, 20014, Finland; Institute of Biomedicine Physiology, University of Eastern Finland, Kuopio, FI-70211, Finland; University of Leuven, Department of Neurosciences, Leuven, 3000, Belgium; Translational Immunology Laboratory, VIB, Leuven, 3000, Belgium; Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Chicago, 60611, IL, United States; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, G128TA, United Kingdom; Endometriosis CaRe Centre, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, OX39DU, United Kingdom; Center for Genomic Regulation, Barcelona, 08003, Spain; Department of Internal Medicine, Lausanne University, Lausanne, 1011, Switzerland; Joint BSCCRG, IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, 08034, Spain; Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, 4000, QLD, Australia; Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, Hong Kong; Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, Hong Kong; Hong Kong Institute of Diabetes and Obesity, Chinese University of Hong Kong, Hong Kong, Hong Kong; Department of Obstetrics and Gynaecology, Chinese University of Hong Kong, Hong Kong, Hong Kong; Department of Human Genetics and Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, MI, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, 02115, MA, United States; Program in Medical and Population Genetics, Broad Institute of Harvard, Cambridge, 02142, MA, United States; European Centre for Environment and Human Health, University of Exeter, Truro, TR13HD, United Kingdom; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, BS82BN, United Kingdom; School of Social and Community Medicine, University of Bristol, Bristol, BS82BN, United Kingdom; Department of Genomics of Common Disease, School of Public Health, London, SW72AZ, United Kingdom; IFB Adiposity Diseases, University of Leipzig, Leipzig, 04103, Germany; Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB101HH, United Kingdom; FISABIO, Universitat Jaume Universitat de València, Joint Research Unit of Epidemiology and Environmental Health, Valencia, 46020, Spain; Children's Obesity Clinic, Department of Pediatrics, Copenhagen University, Holbæk, DK-4300, Denmark; Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, 1010, Switzerland; Danish Center for Neonatal Screening, Statens Serum Institute, Copenhagen, 2300, Denmark; Department for Congenital Disorders, Statens Serum Institute, Copenhagen, 2300, Denmark; Computer Sciences Department, Barcelona Supercomputing Center, Barcelona, 08034, Spain; Institució Catalana de Recerca i Estudis Avancąts, Barcelona, 08010, Spain; Department of Internal Medicine, University Medical Center Rotterdam, Rotterdam, 3015, Netherlands; BHF Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, EH164TJ, United Kingdom; Department of Medicine, Division of Endocrinology, Feinberg School of Medicine, Chicago, 60611, IL, United States; Medical Department, University of Leipzig, Leipzig, 04103, Germany; Department of Clinical Physiology and Nuclear Medicine, Kuopio University, Kuopio, FI-70029, Finland; Kuopio Research Institute of Exercise Medicine, Kuopio, FI-70100, Finland; Pediatric Research Center, Department of Womeńs and Child Health, University of Leipzig, Leipzig, 04103, Germany; Novo Nordisk Foundation Center for Basic Metabolic Research, Health and Medical Sciences Faculty, University of Copenhagen, Copenhagen, 2200, Denmark; Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospital, Capital Region, Copenhagen, 2000, Denmark; Department of Pediatrics, Turku University Hospital, Turku, 20521, Finland; Department of Physiology, University of Turku, Turku, 20014, Finland; Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, Turku, 20014, Finland; Department of Clinical Physiology and Nuclear Medicine, Turku University, Turku, 20521, Finland; Department of Statistics and Applied Probability, National University of Singapore, Singapore, 117546, Singapore; Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore; Singapore Eye Research Institute, Singapore, 168751, Singapore; Department of Clinical Medicine, University of Copenhagen, Copenhagen, 2200, Denmark; Department of Medicine, Stanford School of Medicine, Stanford, 94305, CA, United States; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH42XU, United Kingdom; EMGO Institute for Health, University Medical, Amsterdam, 1081, Netherlands; Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, 1870, Denmark; Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, 90014, Finland; Biocenter Oulu, University of Oulu, Oulu, 90014, Finland; School of Medicine and Pharmacology, Royal Perth Hospital Unit, University of Western Australia, Perth, 6000, WA, Australia; Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, University Hospital Munich, Munich, 80336, Germany; Department of Nutrition, University of North Carolina, Chapel Hill, 27599, NC, United States; USC Office of Population Studies Foundation Inc, University of San Carlos, Cebu City, 6000, Philippines; Department of Nutrition and Dietetics, University of San Carlos, Cebu City, 6000, Philippines; National Institute for Health and Welfare, Helsinki, 00271, Finland; Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, 00014, Finland; Folkhälsan Research Center, Helsinki, 00250, Finland; Department of Clinical Physiology, Tampere University Hopital, Tampere, 33521, Finland; Department of Clinical Physiology, University of Tampere, School of Medicine, Tampere, 33014, Finland; Division of Medicine, Turku University Hospital, Turku, 20521, Finland; Department of Medicine, University of Turku, Turku, 20014, Finland; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, 2333, Netherlands; Epidemiology Section, BESC Department, King Faisal Specialist Hospital, Riyadh, 12713, Saudi Arabia; Research Center for Prevention, Health Capital Region, Copenhagen University, Glostrup, 2600, Denmark; Population Policy and Practice, UCL Institute of Child Health, University College London, London, WC1N1EH, United Kingdom; Centre for Population Health Research, School of Health Sciences, University of South Australia, Adelaide, 5001, SA, Australia; South Australian Health, Medical Research Institute, Adelaide, 5000, SA, Australia; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, PA, United States; Department of Epidemiology and Biostatistics, Centre for Environment and Health, School of Public Health, London, SW72AZ, United Kingdom; Unit of Primary Care, Oulu University Hospital, Oulu, 90220, Finland; Division of Endocrinology, Children's Hospital of Philadelphia, Philadelphia, 19104, PA, United States; Department of Endocrinology Rigshospitalet, Copenhagen, 2100, Denmark; AstraZeneca Innovative Medicines, Mölndal, 43183, Sweden; Department of Biostatistics, University of Liverpool, Liverpool, L693GA, United Kingdom; Estonian Genome Center, University of Tartu, Tartu, 50090, Estonia; Department of Paediatrics, University of Cambridge, Cambridge, CB20QQ, United Kingdom; Oxford National Institute for Health Research, Biomedical Research Centre, Churchill Hospital, Oxford, OX37LE, United Kingdom
