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Research Article

Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts

  • Karani S. Vimaleswaran equal contributor,

    equal contributor Contributed equally to this work with: Karani S. Vimaleswaran, Diane J. Berry, Elina Hyppönen

    Affiliation: Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, United Kingdom

    X
  • Diane J. Berry equal contributor,

    equal contributor Contributed equally to this work with: Karani S. Vimaleswaran, Diane J. Berry, Elina Hyppönen

    Affiliation: Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, United Kingdom

    X
  • Chen Lu,

    Affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America

    X
  • Emmi Tikkanen,

    Affiliations: Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland, National Institute for Health and Welfare, Helsinki, Finland

    X
  • Stefan Pilz,

    Affiliations: Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria, Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands

    X
  • Linda T. Hiraki,

    Affiliation: Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America

    X
  • Jason D. Cooper,

    Affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom

    X
  • Zari Dastani,

    Affiliation: Department of Epidemiology, Biostatistics and Occupational Health, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

    X
  • Rui Li,

    Affiliation: Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

    X
  • Denise K. Houston,

    Affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America

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  • Andrew R. Wood,

    Affiliation: Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom

    X
  • Karl Michaëlsson,

    Affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    X
  • Liesbeth Vandenput,

    Affiliation: Center for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

    X
  • Lina Zgaga,

    Affiliations: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom, Andrija Stampar School of Public Health, Medical School University of Zagreb, Zagreb, Croatia

    X
  • Laura M. Yerges-Armstrong,

    Affiliation: University of Maryland School of Medicine, Division of Endocrinology, Baltimore, Maryland, United States of America

    X
  • Mark I. McCarthy,

    Affiliations: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom, Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, United Kingdom

    X
  • Josée Dupuis,

    Affiliations: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America, National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America

    X
  • Marika Kaakinen,

    Affiliation: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland

    X
  • Marcus E. Kleber,

    Affiliation: LURIC Study non-profit LLC, Freiburg, Germany and Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany

    X
  • Karen Jameson,

    Affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom

    X
  • Nigel Arden,

    Affiliations: NIHR Musculoskeletal BRU, Botnar Research Centre, Oxford, United Kingdom, MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom

    X
  • Olli Raitakari,

    Affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland

    X
  • Jorma Viikari,

    Affiliation: Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland

    X
  • Kurt K. Lohman,

    Affiliation: Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America

    X
  • Luigi Ferrucci,

    Affiliation: Clinical Research Branch, Harbor Hospital, Baltimore, Maryland, United States of America

    X
  • Håkan Melhus,

    Affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    X
  • Erik Ingelsson,

    Affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    X
  • Liisa Byberg,

    Affiliation: Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    X
  • Lars Lind,

    Affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    X
  • Mattias Lorentzon,

    Affiliation: Center for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

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  • Veikko Salomaa,

    Affiliation: National Institute for Health and Welfare, Helsinki, Finland

    X
  • Harry Campbell,

    Affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom

    X
  • Malcolm Dunlop,

    Affiliations: Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom, MRC Human Genetics Unit Western General Hospital Edinburgh, United Kingdom

    X
  • Braxton D. Mitchell,

    Affiliation: University of Maryland School of Medicine, Division of Endocrinology, Baltimore, Maryland, United States of America

    X
  • Karl-Heinz Herzig,

    Affiliations: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland, Institute of Biomedicine, University of Oulu, Oulu, Finland, Department of Psychiatry, Kuopio University Hospital, Kuopio, Finland

    X
  • Anneli Pouta,

    Affiliation: Department of Public Health Science and General Practice, University of Oulu, Oulu, Finland

    X
  • Anna-Liisa Hartikainen,

    Affiliation: Department of Obstetrics and Gynaecology and Public Health and General Practice, University of Oulu, Oulu, Finland

    X
  • the Genetic Investigation of Anthropometric Traits (GIANT) consortium,

    Membership of the Genetic Investigation of Anthropometric Traits (GIANT) consortium is provided in the Acknowledgments.

    X
  • Elizabeth A. Streeten,

    Affiliation: University of Maryland School of Medicine, Division of Endocrinology, Baltimore, Maryland, United States of America

    X
  • Evropi Theodoratou,

    Affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom

    X
  • Antti Jula,

    Affiliation: National Institute for Health and Welfare, Helsinki, Finland

    X
  • Nicholas J. Wareham,

    Affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom

    X
  • Claes Ohlsson,

    Affiliation: Center for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

    X
  • Timothy M. Frayling,

    Affiliation: Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom

    X
  • Stephen B. Kritchevsky,

    Affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America

    X
  • Timothy D. Spector,

    Affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom

    X
  • J. Brent Richards,

    Affiliations: Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada, Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom

    X
  • Terho Lehtimäki,

    Affiliation: Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and University of Tampere, Tampere, Finland

    X
  • Willem H. Ouwehand,

    Affiliations: Department of Haematology, University of Cambridge, United Kingdom, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom, NHS Blood and Transplant, Cambridge, United Kingdom

    X
  • Peter Kraft,

    Affiliation: Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America

    X
  • Cyrus Cooper,

    Affiliation: MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom

    X
  • Winfried März,

    Affiliations: Synlab Academy, Mannheim, Germany, Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany

    X
  • Chris Power,

    Affiliation: Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, United Kingdom

    X
  • Ruth J. F. Loos,

    Affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom

    X
  • Thomas J. Wang,

    Affiliation: Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America

    X
  • Marjo-Riitta Järvelin,

    Affiliations: Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland, Department of Biostatistics and Epidemiology, School of Public Health, MRC-HPA Centre for Environment and Health, Imperial College, Faculty of Medicine, London, United Kingdom, Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland

    X
  • John C. Whittaker,

    Affiliations: Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom, Quantitative Sciences, GlaxoSmithKline, Stevenage, United Kingdom

    X
  • Aroon D. Hingorani,

    Affiliations: Genetic Epidemiology Group, Department of Epidemiology and Public Health, Division of Population Health, University College London, London, United Kingdom, Division of Medicine, Centre for Clinical Pharmacology, University College London, London, United Kingdom

    X
  • Elina Hyppönen equal contributor mail

    equal contributor Contributed equally to this work with: Karani S. Vimaleswaran, Diane J. Berry, Elina Hyppönen

    e.hypponen@ucl.ac.uk

    Affiliation: Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, United Kingdom

    X
  • Published: February 05, 2013
  • DOI: 10.1371/journal.pmed.1001383
  • Featured in PLOS Collections

About the Authors

Karani S. Vimaleswaran, Diane J. Berry, Chris Power, Elina Hyppönen
Centre for Paediatric Epidemiology and Biostatistics and MRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, London, United Kingdom
Chen Lu, Josée Dupuis
Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America
Emmi Tikkanen
Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
Emmi Tikkanen, Veikko Salomaa, Antti Jula
National Institute for Health and Welfare, Helsinki, Finland
Stefan Pilz
Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria
Stefan Pilz
Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Centre, Amsterdam, The Netherlands
Linda T. Hiraki, Peter Kraft
Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America
Jason D. Cooper
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
Zari Dastani
Department of Epidemiology, Biostatistics and Occupational Health, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
Rui Li, J. Brent Richards
Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada
Denise K. Houston, Stephen B. Kritchevsky
Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America
Andrew R. Wood, Timothy M. Frayling
Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, United Kingdom
Karl Michaëlsson, Liisa Byberg
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
Liesbeth Vandenput, Mattias Lorentzon, Claes Ohlsson
Center for Bone and Arthritis Research, Department of Internal Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
Lina Zgaga, Harry Campbell, Evropi Theodoratou
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom
Lina Zgaga
Andrija Stampar School of Public Health, Medical School University of Zagreb, Zagreb, Croatia
Laura M. Yerges-Armstrong, Braxton D. Mitchell, Elizabeth A. Streeten
University of Maryland School of Medicine, Division of Endocrinology, Baltimore, Maryland, United States of America
Mark I. McCarthy
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom
Mark I. McCarthy
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Mark I. McCarthy
Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, United Kingdom
Josée Dupuis
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, United States of America
Marika Kaakinen, Karl-Heinz Herzig, Marjo-Riitta Järvelin
Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland
Marcus E. Kleber
LURIC Study non-profit LLC, Freiburg, Germany and Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany
Karen Jameson, Nigel Arden, Cyrus Cooper
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, United Kingdom
Nigel Arden
NIHR Musculoskeletal BRU, Botnar Research Centre, Oxford, United Kingdom
Olli Raitakari
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology and Nuclear Medicine, University of Turku and Turku University Hospital, Turku, Finland
Jorma Viikari
Department of Medicine, University of Turku and Turku University Hospital, Turku, Finland
Kurt K. Lohman
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston Salem, North Carolina, United States of America
Luigi Ferrucci
Clinical Research Branch, Harbor Hospital, Baltimore, Maryland, United States of America
Håkan Melhus, Lars Lind
Department of Medical Sciences, Uppsala University, Uppsala, Sweden
Erik Ingelsson
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Malcolm Dunlop
Colon Cancer Genetics Group and Academic Coloproctology, Institute of Genetics and Molecular Medicine, University of Edinburgh, United Kingdom
Malcolm Dunlop
MRC Human Genetics Unit Western General Hospital Edinburgh, United Kingdom
Karl-Heinz Herzig
Institute of Biomedicine, University of Oulu, Oulu, Finland
Karl-Heinz Herzig
Department of Psychiatry, Kuopio University Hospital, Kuopio, Finland
Anneli Pouta
Department of Public Health Science and General Practice, University of Oulu, Oulu, Finland
Anna-Liisa Hartikainen
Department of Obstetrics and Gynaecology and Public Health and General Practice, University of Oulu, Oulu, Finland
Nicholas J. Wareham, Ruth J. F. Loos
MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
Timothy D. Spector, J. Brent Richards
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
Terho Lehtimäki
Department of Clinical Chemistry, Fimlab Laboratories, Tampere University Hospital and University of Tampere, Tampere, Finland
Willem H. Ouwehand
Department of Haematology, University of Cambridge, United Kingdom
Willem H. Ouwehand
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
Willem H. Ouwehand
NHS Blood and Transplant, Cambridge, United Kingdom
Winfried März
Synlab Academy, Mannheim, Germany
Winfried März
Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, Germany
Thomas J. Wang
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts, United States of America
Marjo-Riitta Järvelin
Department of Biostatistics and Epidemiology, School of Public Health, MRC-HPA Centre for Environment and Health, Imperial College, Faculty of Medicine, London, United Kingdom
Marjo-Riitta Järvelin
Department of Children, Young People and Families, National Institute for Health and Welfare, Oulu, Finland
John C. Whittaker
Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom
John C. Whittaker
Quantitative Sciences, GlaxoSmithKline, Stevenage, United Kingdom
Aroon D. Hingorani
Genetic Epidemiology Group, Department of Epidemiology and Public Health, Division of Population Health, University College London, London, United Kingdom
Aroon D. Hingorani
Division of Medicine, Centre for Clinical Pharmacology, University College London, London, United Kingdom

Corresponding Author

Email: e.hypponen@ucl.ac.uk

Competing Interests

LTH is currently supported by a Canada Institute of Research (CIHR) Fellowship award. CC has received honoraria and consulting fees from Amgen, Eli Lilly, Medtronic, Merck, Novartis, and Servier. WM is an employee of synlab laboratory services GmbH. Synlab offers vitamin D testing. TJW is on the scientific advisory board for Diasorin Inc. and has received research support from them. JCW is 90% employed by GlaxoSmithKline (GSK) whilst maintaining a 10% appointment at London School of Hygiene & Tropical Medicine (LSHTM), and holds GSK shares. All other authors declare that no competing interests exist.

Author Contributions

Conceived and designed the experiments: KSV DJB MM OR JV BDM EAM NJW TM TL WHO CC TJW MRJ JCW ADH EH. Performed the experiments: KSV DJB CL ET SP LTH JDC KHL ZD RL ARW KM LZ LMY JD MCK KJ VS BDM EAS DKH TL PK CC RJFL JCW ADH EH. Analyzed the data: KSV DJB CL ET SP LTH JDC KHL ZD RL ARW KM LZ LMY JD MCK KJ VS BDM EAS DKH TL PK CC RJFL JCW ADH EH. Contributed reagents/materials/analysis tools: KSV DJB SP LTH KM LMY MM JD MK NA OR JV SBK HM EI LB LL VS BDM KH EAS DKH TL PK CC WM RJFL CP MRJ JCW ADH EH. Wrote the first draft of the manuscript: KSV DJB EH. Contributed to the writing of the manuscript: KSV DJB EH. ICMJE criteria for authorship read and met: KSV DJB CL ET SP LTH JDC ZD RL DKH ARW KM LV LZ LMY MM JD MK MEK KJ NA OR JV KKL LF HM EI LB LL ML VS HC MD BDM KHH AP ALH EAS ET AJ NJW CO TMF SBK TDS JBR TL WHO PK CC WM CP RJFL TJW MRJ JCW ADH EH. Agree with manuscript results and conclusions: KSV DJB CL ET SP LTH JDC ZD RL DKH ARW KM LV LZ LMY MM JD MK MEK KJ NA OR JV KKL LF HM EI LB LL ML VS HC MD BDM KHH AP ALH EAS ET AJ NJW CO TMF SBK TDS JBR TL WHO PK CC WM CP RJFL TJW MRJ JCW ADH EH. Obtained the data: KSV DJB SP LTH ZD RL KM LV MM MK MCK KJ NA OR JV SBK LF HM EI LB LL ML VS HC MD BDM AP AH ET NJW CO TMF DKH JBR TL WHO PK CC WM CP ADH MRJ EH. Provided the administrative, technical, or material support: KSV DJB KM MK OR JV SBK LF HM EI LL VS TMF DKH TL CP EH. Supervised the study: JD OR JV SBK HC MD BDM EAS AJ ET TS TMF JBR TL TJW MRJ JCW ADH EH.