Article | Published:

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors

Nature Geneticsvolume 51pages804814 (2019) | Download Citation

Abstract

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.

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Data availability

The genotype and phenotype data are available on application from the UK Biobank (http://www.ukbiobank.ac.uk/). Individual cohorts participating in the EGG Consortium should be contacted directly as each cohort has different data access policies. GWAS summary statistics from this study are available via the EGG website (https://egg-consortium.org/).

Code availability

Custom-written code is available on request from N.M.W. (e-mail: n.warrington@uq.edu.au).

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

Full acknowledgements and supporting grant details can be found in the Supplementary Information.

Author information

Author notes

  1. These authors contributed equally: Nicole M. Warrington, Robin N. Beaumont, Momoko Horikoshi, Felix R. Day, Øyvind Helgeland.

  2. These authors jointly supervised this work: Ken K. Ong, Mark I. McCarthy, John R. B. Perry, David M. Evans, Rachel M. Freathy.

  3. A list of members and affiliations appears in the Supplementary Note.

Affiliations

  1. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia

    • Nicole M. Warrington
    • , Zhen Qiao
    •  & David M. Evans
  2. Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Royal Devon and Exeter Hospital, Exeter, UK

    • Robin N. Beaumont
    • , Andrew R. Wood
    • , Jessica Tyrrell
    • , Marcus A. Tuke
    • , Hanieh Yaghootkar
    • , Katherine S. Ruth
    • , Samuel E. Jones
    • , Anna Murray
    • , Michael N. Weedon
    • , Andrew T. Hattersley
    • , Timothy M. Frayling
    •  & Rachel M. Freathy
  3. RIKEN Centre for Integrative Medical Sciences, Laboratory for Endocrinology, Metabolism and Kidney Diseases, Yokohama, Japan

    • Momoko Horikoshi
  4. Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

    • Momoko Horikoshi
    • , Anubha Mahajan
    • , Neil R. Robertson
    • , N. William Rayner
    • , Vasiliki Lagou
    • , Kyle J. Gaulton
    • , Juan Fernandez-Tajes
    • , Natalie R. van Zuydam
    • , Inga Prokopenko
    • , Andrew P. Morris
    •  & Mark I. McCarthy
  5. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

    • Momoko Horikoshi
    • , Anubha Mahajan
    • , Neil R. Robertson
    • , N. William Rayner
    • , Amanda J. Bennett
    • , Natalie R. van Zuydam
    •  & Mark I. McCarthy
  6. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK

    • Felix R. Day
    • , Claudia Langenberg
    • , Jian’an Luan
    • , Robert A. Scott
    • , Jing Hua Zhao
    • , Nicholas J. Wareham
    • , Ken K. Ong
    •  & John R. B. Perry
  7. KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway

    • Øyvind Helgeland
    • , Marc Vaudel
    • , Pål R. Njølstad
    •  & Stefan Johansson
  8. Department of Pediatrics, Haukeland University Hospital, Bergen, Norway

    • Øyvind Helgeland
    •  & Pål R. Njølstad
  9. Department of Genetics and Bioinformatics, Domain of Health Data and Digitalisation, Norwegian Institute of Public Health, Oslo, Norway

    • Øyvind Helgeland
    •  & Bo Jacobsson
  10. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • Charles Laurin
    • , Lavinia Paternoster
    • , Rebecca C. Richmond
    • , Caroline L. Relton
    • , Gibran Hemani
    • , Susan M. Ring
    • , Thorkild I. A. Sørensen
    • , George Davey Smith
    • , Nicholas J. Timpson
    • , Debbie A. Lawlor
    • , David M. Evans
    •  & Rachel M. Freathy
  11. Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK

    • Charles Laurin
    • , Rebecca C. Richmond
    • , Caroline L. Relton
    • , Gibran Hemani
    • , Susan M. Ring
    • , George Davey Smith
    • , Nicholas J. Timpson
    • , Debbie A. Lawlor
    •  & David M. Evans
  12. Department of Obstetrics and Gynecology, Sahlgrenska University Hospital Östra, Gothenburg, Sweden

    • Jonas Bacelis
    •  & Bo Jacobsson
  13. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Shouneng Peng
    •  & Ke Hao
  14. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Shouneng Peng
    •  & Ke Hao
  15. Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark

    • Bjarke Feenstra
    • , Frank Geller
    •  & Mads Melbye
  16. European Centre for Environment and Human Health, University of Exeter, Truro, UK

    • Jessica Tyrrell
  17. Wellcome Sanger Institute, Hinxton, UK

    • N. William Rayner
    • , Kalliope Panoutsopoulou
    •  & Eleftheria Zeggini
  18. Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway

    • Gunn-Helen Moen
  19. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    • Gunn-Helen Moen
  20. Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA

    • Carmen J. Marsit
  21. Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Jia Chen
  22. Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    • Michael Nodzenski
    •  & Denise M. Scholtens
  23. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Theresia M. Schnurr
    • , Niels Grarup
    • , Tarunveer S. Ahluwalia
    • , Christian T. Have
    • , Emil V. R. Appel
    • , Cilius E. Fonvig
    • , Caecilie Trier
    • , Jens-Christian Holm
    • , Thorkild I. A. Sørensen
    • , Torben Hansen
    •  & Oluf Pedersen
  24. Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

    • Mohammad H. Zafarmand
    •  & Tanja G. M. Vrijkotte
  25. Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

    • Mohammad H. Zafarmand
  26. Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Jonathan P. Bradfield
    • , Frank D. Mentch
    • , Hakon Hakonarson
    •  & Struan F. A. Grant
  27. Quantinuum Research, San Diego, CA, USA

    • Jonathan P. Bradfield
  28. The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    • Marjolein N. Kooijman
    • , Carolina Medina-Gomez
    • , Fernando Rivadeneira
    • , Janine F. Felix
    • , Vincent W. V. Jaddoe
    •  & André G. Uitterlinden
  29. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    • Marjolein N. Kooijman
    • , Elisabeth M. van Leeuwen
    • , Carolina Medina-Gomez
    • , Sara M. Willems
    • , Cornelia M. van Duijn
    • , Fernando Rivadeneira
    • , Albert Hofman
    • , Janine F. Felix
    • , Vincent W. V. Jaddoe
    •  & André G. Uitterlinden
  30. Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    • Marjolein N. Kooijman
    • , Janine F. Felix
    •  & Vincent W. V. Jaddoe
  31. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands

    • Ruifang Li-Gao
    • , Hugoline G. de Haan
    • , Frits R. Rosendaal
    •  & Dennis O. Mook-Kanamori
  32. Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark

    • Tarunveer S. Ahluwalia
    • , Jakob Stokholm
    • , Rebecca K. Vinding
    • , Bo L. Chawes
    • , Hans Bisgaard
    •  & Klaus Bønnelykke
  33. Steno Diabetes Center Copenhagen, Gentofte, Denmark

    • Tarunveer S. Ahluwalia
  34. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland

    • Rico Rueedi
  35. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    • Rico Rueedi
    •  & Zoltán Kutalik
  36. Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland

    • Ville Huikari
    • , Sylvain Sebert
    •  & Marjo-Riitta Järvelin
  37. Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    • Jouke-Jan Hottenga
    • , Gonneke Willemsen
    • , Hamdi Mbarek
    • , Meike Bartels
    • , Eco J. C. N. de Geus
    •  & Dorret I. Boomsma
  38. Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    • Jouke-Jan Hottenga
    • , Gonneke Willemsen
    • , Hamdi Mbarek
    • , Catharina E. M. van Beijsterveldt
    • , Meike Bartels
    • , Eco J. C. N. de Geus
    •  & Dorret I. Boomsma
  39. Amsterdam Public Health, Amsterdam, the Netherlands

    • Jouke-Jan Hottenga
    • , Gonneke Willemsen
    • , Hamdi Mbarek
    • , Meike Bartels
    • , Eco J. C. N. de Geus
    •  & Dorret I. Boomsma
  40. Department of Clinical Chemistry, Fimlab Laboratories, Tampere, Finland

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  41. Department of Clinical Chemistry, Finnish Cardiovascular Research Center–Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    • Leo-Pekka Lyytikäinen
    •  & Terho Lehtimäki
  42. Section of Epidemiology and Biostatistics, School of Population Health, University of Auckland, Auckland, New Zealand

    • Alana Cavadino
  43. Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, University College London, London, UK

    • Alana Cavadino
    • , Christine Power
    •  & Elina Hyppönen
  44. Department of Twin Research, King’s College London, St. Thomas’ Hospital, London, UK

    • Sarah Metrustry
    •  & Tim D. Spector
  45. Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Diana L. Cousminer
    • , Hakon Hakonarson
    •  & Struan F. A. Grant
  46. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Diana L. Cousminer
    •  & Struan F. A. Grant
  47. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    • Ying Wu
    •  & Karen L. Mohlke
  48. Institute of Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany

    • Elisabeth Thiering
    • , Marie Standl
    •  & Joachim Heinrich
  49. Division of Metabolic and Nutritional Medicine, Dr. von Hauner Children’s Hospital, University of Munich Medical Center, Munich, Germany

    • Elisabeth Thiering
  50. School of Medicine and Public Health, Faculty of Medicine and Health, The University of Newcastle, Newcastle, New South Wales, Australia

    • Carol A. Wang
    •  & Craig E. Pennell
  51. Center for Genomic Regulation, Barcelona Institute of Science and Technology, Barcelona, Spain

    • Natalia Vilor-Tejedor
  52. Barcelonabeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain

    • Natalia Vilor-Tejedor
  53. Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    • Peter K. Joshi
    • , Katharina E. Schraut
    • , Harry Campbell
    •  & James F. Wilson
  54. QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Brisbane, Queensland, Australia

    • Jodie N. Painter
    • , Penelope A. Lind
    • , Sarah E. Medland
    •  & Grant W. Montgomery
  55. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    • Ioanna Ntalla
  56. Department of Genes and Environment, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway

    • Ronny Myhre
  57. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland

    • Niina Pitkänen
    • , Katja Pahkala
    •  & Olli T. Raitakari
  58. Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland

    • Raimo Joro
    • , Mustafa Atalay
    • , Aino-Maija Eloranta
    •  & Timo A. Lakka
  59. Department of Neuroscience, Katholieke Universiteit Leuven, Leuven, Belgium

    • Vasiliki Lagou
  60. VIB Center for Brain and Disease Research, Leuven, Belgium

    • Vasiliki Lagou
  61. ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain

    • Ana Espinosa
    • , Manolis Kogevinas
    • , Mariona Bustamante
    •  & Martine Vrijheid
  62. Universitat Pompeu Fabra, Barcelona, Spain

    • Ana Espinosa
    • , Manolis Kogevinas
    • , Mariona Bustamante
    •  & Martine Vrijheid
  63. CIBER de Epidemiología y Salud Pública, Madrid, Spain

    • Ana Espinosa
    • , Loreto Santa-Marina
    • , Manolis Kogevinas
    • , Mario Murcia
    • , Mariona Bustamante
    •  & Martine Vrijheid
  64. Hospital del Mar Medical Research Institute, Barcelona, Spain

    • Ana Espinosa
    •  & Manolis Kogevinas
  65. Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK

    • Sheila J. Barton
    •  & Hazel M. Inskip
  66. NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

    • Hazel M. Inskip
  67. Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK

    • John W. Holloway
  68. Subdirección de Salud Pública y Adicciones de Gipuzkoa, San Sebastián, Spain

    • Loreto Santa-Marina
  69. Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain

    • Loreto Santa-Marina
  70. Sidra Medicine Research Department, Sidra Medicine, Doha, Qatar

    • Xavier Estivill
  71. Genomics Unit, Dexeus Woman’s Health, Barcelona, Spain

    • Xavier Estivill
  72. Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Western Australia, Australia

    • Wei Ang
    •  & Julie A. Marsh
  73. Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany

    • Christoph Reichetzeder
  74. Department of Life Sciences and Biotechnology, Genetic Section, University of Ferrara, Ferrara, Italy

    • Letizia Marullo
  75. Fifth Department of Medicine, University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany

    • Berthold Hocher
  76. Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China

    • Berthold Hocher
  77. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    • Kathryn L. Lunetta
  78. Framingham Heart Study, Framingham, MA, USA

    • Kathryn L. Lunetta
    •  & Joanne M. Murabito
  79. Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    • Joanne M. Murabito
  80. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, USA

    • Leda Chatzi
  81. Centre de recherche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada

    • Catherine Allard
    •  & Luigi Bouchard
  82. ECOGENE-21 and Lipid Clinic, Chicoutimi Hospital, Saguenay, Quebec, Canada

    • Luigi Bouchard
  83. Department of Biochemistry, Université de Sherbrooke, Sherbrooke, Quebec, Canada

    • Luigi Bouchard
  84. Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, USA

    • Marie-France Hivert
  85. Diabetes Center, Massachusetts General Hospital, Boston, MA, USA

    • Marie-France Hivert
  86. Department of Medicine, Universite de Sherbrooke, Sherbooke, Quebec, Canada

    • Marie-France Hivert
  87. Human Genetics Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • Ge Zhang
    •  & Louis J. Muglia
  88. 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, USA

    • Ge Zhang
    •  & Louis J. Muglia
  89. March of Dimes Prematurity Research Center Ohio Collaborative, Cincinnati, OH, USA

    • Ge Zhang
    •  & Louis J. Muglia
  90. Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland

    • Jani Heikkinen
    •  & Elisabeth E. Widén
  91. Department of Public Health, Section of Epidemiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Camilla S. Morgen
    •  & Thorkild I. A. Sørensen
  92. Bioinformatics Laboratory, Clinical Epidemiology, Biostatistics and Bioinformatics, Amsterdam Public Health Research Institute, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

    • Antoine H. C. van Kampen
    •  & Barbera D. C. van Schaik
  93. Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands

    • Antoine H. C. van Kampen
  94. Department of Pediatrics, University of California San Diego, La Jolla, CA, USA

    • Kyle J. Gaulton
  95. Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

    • Carolina Medina-Gomez
    • , Fernando Rivadeneira
    •  & André G. Uitterlinden
  96. Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland

    • Zoltán Kutalik
  97. Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne, Switzerland

    • Pedro Marques-Vidal
    •  & Peter Vollenweider
  98. Medical Research Council Unit for Lifelong Health and Ageing at UCL, Institute of Cardiovascular Sciences, University College London, London, UK

    • Shikta Das
  99. Amsterdam Reproduction and Development, Amsterdam, the Netherlands

    • Hamdi Mbarek
    •  & Dorret I. Boomsma
  100. Institute of Genetic Epidemiology, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany

    • Martina Müller-Nurasyid
  101. Department of Internal Medicine I (Cardiology), Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany

    • Martina Müller-Nurasyid
  102. Division of Genetic Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Faculty of Medicine, Ludwig-Maximilians-University Munich, Munich, Germany

    • Martina Müller-Nurasyid
  103. Children’s Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark

    • Cilius E. Fonvig
    • , Caecilie Trier
    •  & Jens-Christian Holm
  104. Hans Christian Andersen Children’s Hospital, Odense University Hospital, Odense, Denmark

    • Cilius E. Fonvig
  105. FISABIO–Universitat Jaume I–Universitat de València, Joint Research Unit of Epidemiology and Environmental Health, Valencia, Spain

    • Mario Murcia
  106. Joint BSC–CGR–IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain

    • Sílvia Bonas-Guarch
    • , Josep M. Mercader
    • , Friman Sánchez
    •  & David Torrents
  107. Danish Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    • David M. Hougaard
  108. Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    • Josep M. Mercader
  109. Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Josep M. Mercader
  110. Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark

    • Allan Linneberg
    •  & Allan A. Vaag
  111. Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark

    • Allan Linneberg
  112. NIHR Exeter Clinical Research Facility, University of Exeter College of Medicine and Health and Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

    • Beverley M. Shields
    • , Bridget A. Knight
    •  & Andrew T. Hattersley
  113. Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore, Singapore

    • Jin-Fang Chai
    • , Yik-Ying Teo
    •  & Seang-Mei Saw
  114. Computer Sciences Department, Barcelona Supercomputing Center, Barcelona, Spain

    • Friman Sánchez
  115. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

    • David Torrents
  116. IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany

    • Peter Kovacs
    • , Michael Stumvoll
    •  & Antje Körner
  117. Section of Genomics of Common Disease, Department of Medicine, Imperial College London, London, UK

    • Inga Prokopenko
  118. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    • Po-Ru Loh
  119. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Po-Ru Loh
  120. Medical Department, University of Leipzig, Leipzig, Germany

    • Anke Tönjes
    •  & Michael Stumvoll
  121. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark

    • Kim F. Michaelsen
  122. Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland

    • Timo A. Lakka
  123. Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

    • Timo A. Lakka
  124. Pediatric Research Center, Department of Women’s andChild Health, University of Leipzig, Leipzig, Germany

    • Wieland Kiess
    •  & Antje Körner
  125. Department of Pediatrics, Turku University Hospital, Turku, Finland

    • Harri Niinikoski
  126. Department of Physiology, University of Turku, Turku, Finland

    • Harri Niinikoski
  127. Paavo Nurmi Centre, Sports and Exercise Medicine Unit, Department of Physical Activity and Health, University of Turku, Turku, Finland

    • Katja Pahkala
  128. Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

    • Olli T. Raitakari
  129. Institute of Translational Genomics, Helmholtz Zentrum München German Research Center for Environmental Health, Neuherberg, Germany

    • Eleftheria Zeggini
  130. Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece

    • George V. Dedoussis
  131. Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore

    • Yik-Ying Teo
  132. Life Sciences Institute, National University of Singapore, Singapore, Singapore

    • Yik-Ying Teo
  133. Singapore Eye Research Institute, Singapore, Singapore

    • Seang-Mei Saw
  134. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • James F. Wilson
  135. Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    • M. Geoffrey Hayes
    •  & William L. Lowe Jr
  136. Quantitative and Systems Genomics Group, Department of Bio and Health Informatics, Technical University of Denmark, Lyngby, Denmark

    • Haja N. Kadarmideen
  137. School of Medicine, Royal Perth Hospital, University of Western Australia, Perth, Western Australia, Australia

    • Lawrence J. Beilin
  138. Institute and Outpatient Clinic for Occupational Social and Environmental Medicine, Inner City Clinic, University Hospital Munich, Ludwig-Maximilians-University Munich, Munich, Germany

    • Joachim Heinrich
  139. Department of Nutrition, University of North Carolina, Chapel Hill, NC, USA

    • Linda S. Adair
  140. USC-Office of Population Studies Foundation, University of San Carlos, Cebu City, Philippines

    • Judith B. Borja
  141. Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines

    • Judith B. Borja
  142. National Institute for Health and Welfare, Helsinki, Finland

    • Johan G. Eriksson
  143. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    • Johan G. Eriksson
  144. Folkhälsan Research Center, Helsinki, Finland

    • Johan G. Eriksson
  145. Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland

    • Mika Kähönen
  146. Department of Clinical Physiology, Finnish Cardiovascular Research Center–Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    • Mika Kähönen
  147. Division of Medicine, Turku University Hospital, Turku, Finland

    • Jorma S. Viikari
  148. Department of Medicine, University of Turku, Turku, Finland

    • Jorma S. Viikari
  149. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK

    • Sylvain Sebert
    •  & Marjo-Riitta Järvelin
  150. Biocenter Oulu, University of Oulu, Oulu, Finland

    • Sylvain Sebert
    •  & Marjo-Riitta Järvelin
  151. Department of Genomics of Complex Diseases, Imperial College London, London, UK

    • Sylvain Sebert
  152. Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    • Jeffrey C. Murray
  153. Department of Medicine, Stanford School of Medicine, Stanford, CA, USA

    • Mads Melbye
  154. Research Unit for Gynaecology and Obstetrics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark

    • Ellen A. Nohr
  155. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands

    • Dennis O. Mook-Kanamori
  156. Research Center for Prevention and Health, Center for Sundhed, Rigshospitalet Glostrup, Copenhagen University, Glostrup, Denmark

    • Charlotta Pisinger
  157. Cardiovascular, Renal and Metabolism, Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden

    • Allan A. Vaag
  158. Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland

    • Marjo-Riitta Järvelin
  159. Department of Life Sciences, College of Health and Life Sciences, Brunel University London, London, UK

    • Marjo-Riitta Järvelin
  160. Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, South Australia, Australia

    • Elina Hyppönen
  161. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    • Elina Hyppönen
  162. NIHR Bristol Biomedical Research Centre, Bristol, UK

    • George Davey Smith
    •  & Debbie A. Lawlor
  163. Department of Biostatistics, University of Liverpool, Liverpool, UK

    • Andrew P. Morris
  164. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Andrew P. Morris
  165. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Hakon Hakonarson
    •  & Struan F. A. Grant
  166. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway

    • Stefan Johansson
  167. Department of Paediatrics, University of Cambridge, Cambridge, UK

    • Ken K. Ong
  168. NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK

    • Mark I. McCarthy

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Consortia

  1. EGG Consortium

    Contributions

    The central analysis and writing team comprised N.M.W., R.N.B., M.H., F.R.D., K.K.O., M.I.M., J.R.B.P., D.M.E. and R.M.F. Statistical analysis was performed by N.M.W., R.N.B., M.H., F.R.D., Ø.H., C.Lau., J.B., S.P., K.H., B.F., A.R.W., A.Mah., J.T., N.R.R., N.W.R., Z.Q., G-H.M., M.Vau., M.N., T.M.S., M.H.Z., J.P.B., N.G., M.N.K., R.L.-G., F.G., T.S.A., L.P., R.R., V.H., J.-J.H., L.-P.L., A.C., S.M., D.L.C., Y.W., E.T., C.A.W., C.T.H., N.V.-T., P.K.J., J.N.P., I.N., R.M., N.P., E.M.v.L., R.J., V.L., R.C.R., A.E., S.J.B., W.A., J.A.M., K.L.L., C.A., G.Z., L.J.M., J.Heik., A.H.C.v.K., B.D.C.v.S., K.J.G., N.R.v.Z., C.M.-G., Z.K., S.D., H.M., E.V.R.A., M.Mur., S.B.-G., D.M.H., J.M.Mer., K.E.S., P.A.L., S.E.M., B.M.S., J.-F.C., K.Pan., F.S., D.T., I.P., M.A.T., H.Y., K.S.R., S.E.J., P.-R.L., A.Mur., M.N.W., E.Z., G.V.D., Y.-Y.T., M.G.H., K.L.M., J.F.F., D.M.S., N.J.T., A.P.M., D.A.L., J.R.B.P., D.M.E. and R.M.F. Genotyping was performed by F.R.D., Ø.H., T.M.S., M.H.Z., N.G., R.L.-G., L.P., J.-J.H., L.-P.L., J.W.H., X.E., L.M., L.B., C.S.M., C.Lan., J.L., R.A.S., J.H.Z., G.H., S.M.R., A.J.B., J.F.-T., C.M.-G., H.G.d.H., F.R.R., Z.K., P.M.-V., H.M., E.V.R.A., M.Bus., M.A., P.K., M.Stu., T.A.L., C.M.v.D., A.K., E.Z., S.-M.S., G.W.M., H.C., J.F.W., T.G.M.V., C.E.P., E.E.W., T.D.S., T.L., P.V., H.B., K.B., J.C.M., F.R., J.F.F., T.H., O.P., A.G.U., M.-R.J., W.L.L., G.D.S., N.J.T., N.J.W., H.H., S.F.A.G., T.M.F., D.A.L., P.R.N., K.K.O., M.I.M., J.R.B.P., D.M.E. and R.M.F. Sample collection and phenotyping were performed by F.R.D., B.F., C.J.M., J.C., J.P.B., M.N.K., R.L.-G., F.G., R.R., I.N., H.M.I., J.W.H., L.S.-M., C.R., B.H., C.L.R., M.Kog., L.C., M.-F.H., C.S.M., F.D.M., C.Lan, J.L., R.A.S., J.H.Z., S.M.R., C.M.-G., H.G.d.H., Z.K., P.M.-V., S.D., G.W., M.M.-N., M.Sta., C.E.F., C.T., C.E.M.v.B., M.Bus., D.M.H., A.L., B.A.K., M.Bar., J.S., R.K.V., S.M.W., B.L.C., A.T., K.F.M., A.-M.E., T.A.L., A.K., H.N., K.Pah., O.T.R., B.J., G.V.D., S.-M.S., G.W.M., J.F.W., T.G.M.V., M.Vri., J.-C.H., L.J.B., C.E.P., L.S.A., J.B.B., J.G.E., E.E.W., A.T.H., T.D.S., M.Käh., J.S.V., T.L., P.V., H.B., K.B., M.Mel., E.A.N., D.O.M.-K., J.F.F., V.W.V.J., C.Pis., A.A.V., M.-R.J., C.Pow., E.H., W.L.L., G.D.S., N.J.W., H.H., S.F.A.G., D.A.L., K.K.O., M.I.M. and J.R.B.P. The study designers and principal investigators included J.P.B., I.N., H.M.I., L.S.-M., X.E., B.H., J.M.Mur., M.Kog., L.C., M.-F.H., F.D.M., M.A., A.T., M.Stu., K.F.M., A.-M.E., T.A.L., C.M.v.D., W.K., A.K., H.N., K.Pah., O.T.R., B.J., E.Z., G.V.D., Y.-Y.T., S.-M.S., G.W.M., H.C., J.F.W., T.G.M.V., M.Vri., E.J.C.N.d.G., H.N.K., J.-C.H., L.J.B., C.E.P., J.Hein., L.S.A., J.B.B., K.L.M., J.G.E., E.E.W., A.T.H., T.D.S., M.Käh., J.S.V., T.L., D.I.B., S.S., P.V., T.I.A.S., H.B., K.B., J.C.M., M.Mel., E.A.N., D.O.M.-K., F.R., A.H., J.F.F., V.W.V.J., T.H., C.Pis., A.A.V., O.P., A.G.U., M.-R.J., C.Pow., E.H., W.L.L., N.J.T., A.P.M., N.J.W., H.H., S.F.A.G., T.M.F., D.A.L., P.R.N., S.J., K.K.O., M.I.M., J.R.B.P. and R.M.F.

    Competing interests

    A.A.V. is an employee of AstraZeneca. S.F.A.G. has received support from GlaxoSmithKline for research that is not related to the study presented in this paper. D.A.L. has received support from Medtronic and Roche Diagnostics for biomarker research that is not related to the study presented in this paper. M.I.M. serves on advisory panels for Pfizer, Novo Nordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, has stock options in Zoe Global, and has received research funding from AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Pfizer, Roche, Sanofi–Aventis, Servier and Takeda.

    Corresponding authors

    Correspondence to David M. Evans or Rachel M. Freathy.

    Supplementary information

    1. Supplementary text and figures

      Supplementary Figs. 1–19, Supplementary Tables 1–4, 16 and 18, and Supplementary Note

    2. Reporting Summary

    3. Supplementary Tables

      Supplementary Tables 5–15, 17 and 19

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    https://doi.org/10.1038/s41588-019-0403-1