Letter | Published:

FTO genotype is associated with phenotypic variability of body mass index

Nature volume 490, pages 267272 (11 October 2012) | Download Citation

Abstract

There is evidence across several species for genetic control of phenotypic variation of complex traits1,2,3,4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5,6,7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9,10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.

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References

  1. 1.

    & Genetic analysis of environmental variation. Genet Res. 92, 381–395 (2010)

  2. 2.

    et al. Cell-to-cell stochastic variation in gene expression is a complex genetic trait. PLoS Genet. 4, e1000049 (2008)

  3. 3.

    , , & Genetic variability in residual variation of body weight and conformation scores in broiler chickens. Poult. Sci. 88, 1156–1161 (2009)

  4. 4.

    , , , & Genomic analysis of QTLs and genes altering natural variation in stochastic noise. PLoS Genet. 7, e1002295 (2011)

  5. 5.

    et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007)

  6. 6.

    et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nature Genet. 39, 724–726 (2007)

  7. 7.

    et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007)

  8. 8.

    et al. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 8, e1001116 (2011)

  9. 9.

    et al. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus. PLoS ONE 5, e14040 (2010)

  10. 10.

    et al. Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. Genomics 99, 132–137 (2012)

  11. 11.

    Selection in different environments: effects on environmental sensitivity (reaction norm) and on mean performance. Genet. Res. 56, 57–70 (1990)

  12. 12.

    & Selection for specific and general response to environmental differences. Heredity 30, 33–40 (1973)

  13. 13.

    & Drosophila bristles and the nature of quantitative genetic variation. Phil. Trans. R. Soc. Lond. B 360, 1513–1527 (2005)

  14. 14.

    et al. Evidence for genetic control of adult weight plasticity in the snail Helix aspersa. Genetics 168, 2089–2097 (2004)

  15. 15.

    , & Genetic variation and quantitative trait loci associated with developmental stability and the environmental correlation between traits in maize. Genet Res. 90, 385–395 (2008)

  16. 16.

    , & Use of genomic models to study genetic control of environmental variance. Genet. Res. 93, 125–138 (2011)

  17. 17.

    & Detecting major genetic loci controlling phenotypic variability in experimental crosses. Genetics 188, 435–447 (2011)

  18. 18.

    , , & On the use of variance per genotype as a tool to identify quantitative trait interaction effects: a report from the Women’s Genome Health Study. PLoS Genet. 6, e1000981 (2010)

  19. 19.

    , & Do the MN and Jk systems influence environmental variability in serum lipid levels? Clin. Genet. 24, 1–14 (1983)

  20. 20.

    & Statistical power to detect genetic loci affecting environmental sensitivity. Behav. Genet. 40, 728–733 (2010)

  21. 21.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999)

  22. 22.

    et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genet. 42, 937–948 (2010)

  23. 23.

    , , , & Variance heterogeneity analysis for detection of potentially interacting genetic loci: method and its limitations. BMC Genet. 11, 92 (2010)

  24. 24.

    et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010)

  25. 25.

    Quantile-specific penetrance of genes affecting lipoproteins, adiposity and height. PLoS ONE 7, e28764 (2012)

  26. 26.

    et al. Modification effects of physical activity and protein intake on heritability of body size and composition. Am. J. Clin. Nutr. 90, 1096–1103 (2009)

  27. 27.

    et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 57, 95–101 (2008)

  28. 28.

    et al. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch. Intern. Med. 168, 1791–1797 (2008)

  29. 29.

    et al. N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chem. Biol. 7, 885–887 (2011)

  30. 30.

    et al. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. Hum. Mol. Genet. 21, 371–383 (2012)

  31. 31.

    The International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007)

  32. 32.

    , , , & A new multipoint method for genom × 10−wide association studies by imputation of genotypes. Nature Genet. 39, 906–913 (2007)

  33. 33.

    , , , & MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet. Epidemiol. 34, 816–834 (2010)

  34. 34.

    , , & GenABEL: an R library for genome-wide association analysis. Bioinformatics 23, 1294–1296 (2007)

  35. 35.

    , & METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010)

  36. 36.

    et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010)

Download references

Acknowledgements

We acknowledge funding from the Australian National Health and Medical Research Council (NHMRC grants 241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672, 613601 and 1011506), the US National Institutes of Health (grants AA07535, AA10248, AA014041, AA13320, AA13321, AA13326, DA12854 and GM057091) and the Australian Research Council (ARC grant DP1093502). A detailed list of acknowledgements by study is provided in the Supplementary Information. We apologize to authors whose work we could not cite owing to space restrictions.

Author information

Affiliations

  1. University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.

    • Jian Yang
    • , Joseph E. Powell
    •  & Peter M. Visscher
  2. Queensland Institute of Medical Research, 300 Herston Road, Brisbane, Queensland 4006, Australia.

    • Jian Yang
    • , Joseph E. Powell
    • , Sarah E. Medland
    • , Dale R. Nyholt
    • , Grant W. Montgomery
    • , Nicholas G. Martin
    •  & Peter M. Visscher
  3. MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge CB2 0QQ, UK.

    • Ruth J. F. Loos
    • , Jing Hua Zhao
    • , Jian’an Luan
    •  & Nicholas J. Wareham
  4. Mount Sinai School of Medicine, New York, New York 10029, USA.

    • Ruth J. F. Loos
  5. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Elizabeth K. Speliotes
  6. Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Elizabeth K. Speliotes
  7. Division of Preventive Medicine, Brigham and Women’s Hospital, 900 Commonwealth Avenue, Boston, Massachusetts 02215, USA.

    • Daniel I. Chasman
    • , Lynda M. Rose
    •  & Paul M. Ridker
  8. Harvard Medical School, Boston, Massachusetts 02215, USA.

    • Daniel I. Chasman
    •  & Paul M. Ridker
  9. deCODE genetics, IS-101 Reykjavik, Iceland.

    • Gudmar Thorleifsson
    • , Valgerdur Steinthorsdottir
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  10. Estonian Genome Center, University of Tartu, Tartu 50410, Estonia.

    • Reedik Mägi
    • , Tõnu Esko
    • , Krista Fischer
    •  & Andres Metspalu
  11. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • Reedik Mägi
    • , Anubha Mahajan
    • , Anuj Goel
    • , Inga Prokopenko
    • , Cecilia M. Lindgren
    • , Hugh Watkins
    •  & Mark I. McCarthy
  12. Hudson Alpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.

    • Lindsay Waite
  13. Icelandic Heart Association, IS-201 Kopavogur, Iceland.

    • Albert Vernon Smith
    •  & Vilmundur Gudnason
  14. University of Iceland, IS-101 Reykjavik, Iceland.

    • Albert Vernon Smith
    •  & Vilmundur Gudnason
  15. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    • Laura M. Yerges-Armstrong
    • , Alan R. Shuldiner
    •  & Jeffrey R. O’Connell
  16. Department of Epidemiology, The University of North Carolina, Chapel Hill, North Carolina 27514, USA.

    • Keri L. Monda
  17. Division of Population Health Sciences & Education, St George’s, University of London, London SW17 0RE, UK.

    • David Hadley
    •  & David P. Strachan
  18. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98101, USA.

    • Guo Li
  19. Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.

    • Karen Kapur
    • , Zoltán Kutalik
    •  & Jacques S. Beckmann
  20. Swiss Institute of Bioinformatics, 1005 Lausanne, Switzerland.

    • Karen Kapur
    •  & Zoltán Kutalik
  21. MRC HGU at the MRC IGMM at the University of Edinburgh, Edinburgh EH8 9AG, UK.

    • Veronique Vitart
    • , Jennifer E. Huffman
    • , Caroline Hayward
    •  & Alan F. Wright
  22. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Sophie R. Wang
    •  & Joel N. Hirschhorn
  23. Divisions of Genetics and Endocrinology and Program in Genomics, Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Sophie R. Wang
    • , Cameron Palmer
    •  & Joel N. Hirschhorn
  24. Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Sophie R. Wang
    • , Cameron Palmer
    •  & Joel N. Hirschhorn
  25. Department of Epidemiology, Subdivison Genetic Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

    • Ayşe Demirkan
    • , Aaron Isaacs
    • , Ben A. Oostra
    •  & Cornelia M. van Duijn
  26. Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.

    • Mary F. Feitosa
    • , Ingrid B. Borecki
    •  & Michael A. Province
  27. Boston University, Boston, Massachusetts 02118, USA.

    • Nancy L. Heard-Costa
    • , Charles White
    • , L. Adrienne Cupples
    •  & Larry D. Atwood
  28. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Anne U. Jackson
    •  & Michael Boehnke
  29. Universität zu Lübeck, Medizinische Klinik II, Ratzeburger Allee 160, 23538 Lübeck, Germany.

    • Michael Preuss
    • , Jeanette Erdmann
    •  & Heribert Schunkert
  30. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, 23562 Lübeck, Germany.

    • Michael Preuss
    •  & Andreas Ziegler
  31. Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden.

    • Joel Eriksson
    • , Mattias Lorentzon
    •  & Claes Ohlsson
  32. Department of Health Sciences, University of Milano, 20133 Milano, Italy.

    • Francesca Frau
    •  & Daniele Cusi
  33. Unit of Genetic Epidemiology & Bioinformatics, Department of Epidemiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

    • Ilja M. Nolte
    •  & Harold Snieder
  34. Department of Endocrinology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands.

    • Jana V. Van Vliet-Ostaptchouk
    •  & Melanie M. Van der Klauw
  35. LifeLines Cohort Study, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

    • Jana V. Van Vliet-Ostaptchouk
    • , Melanie M. Van der Klauw
    •  & Harold Snieder
  36. Department of Biological Psychology, VU University, 1081 BT Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga
    • , Gonneke Willemsen
    • , Jacqueline M. Vink
    • , Eco J. C. de Geus
    •  & Dorret I. Boomsma
  37. Core Genotyping Facility, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.

    • Kevin B. Jacobs
  38. Department of Cardiology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

    • Niek Verweij
    •  & Pim van der Harst
  39. Cardiovascular Medicine, University of Oxford, Oxford OX3 7BN, UK.

    • Anuj Goel
    •  & Hugh Watkins
  40. Department of Internal Medicine, Erasmus MC, Rotterdam 3015GE, The Netherlands.

    • Carolina Medina-Gomez
    • , Karol Estrada
    • , M. Carola Zillikens
    • , André G. Uitterlinden
    •  & Fernando Rivadeneira
  41. Department of Epidemiology, Erasmus MC, Rotterdam 3015GE, The Netherlands.

    • Carolina Medina-Gomez
    • , Karol Estrada
    • , Albert Hofman
    • , Jacqueline C. Witteman
    • , André G. Uitterlinden
    •  & Fernando Rivadeneira
  42. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), 2300 RC Leiden, The Netherlands.

    • Carolina Medina-Gomez
    • , Karol Estrada
    • , Albert Hofman
    • , Jacqueline C. Witteman
    • , André G. Uitterlinden
    •  & Fernando Rivadeneira
  43. Biostatistics - Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Jennifer Lynn Bragg-Gresham
    • , Carlo Sidore
    •  & Goncalo R. Abecasis
  44. Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato 09042, Italy.

    • Serena Sanna
  45. Dipartimento di Scienze Biomediche, Università di Sassari, 07100 SS, Italy.

    • Carlo Sidore
  46. Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.

    • Jonathan Tyrer
  47. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, 17487 Greifswald, Germany.

    • Alexander Teumer
    •  & Georg Homuth
  48. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7BN, UK.

    • Inga Prokopenko
    •  & Mark I. McCarthy
  49. Department of Twin Research and Genetic Epidemiology, King’s College London, Lambeth Palace Road, London SE1 7EH, UK.

    • Massimo Mangino
    •  & Tim D. Spector
  50. Department of Medicine, Stanford University School of Medicine, Stanford 94305, California, USA.

    • Themistocles L. Assimes
  51. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.

    • Alan R. Shuldiner
  52. Pathology and Laboratory Medicine, University of Western Australia, Nedlands Western Australia 6009, Australia.

    • Jennie Hui
    •  & John P. Beilby
  53. Molecular Genetics, PathWest Laboratory Medicine WA, University of Western Australia, Nedlands Western Australia 6009, Australia.

    • Jennie Hui
    •  & John P. Beilby
  54. School of Population Health, University of Western Australia, Nedlands Western Australia 6009, Australia.

    • Jennie Hui
  55. School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.

    • Wendy L. McArdle
  56. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, SE-171 77 Stockholm, Sweden.

    • Per Hall
    • , Henrik Grönberg
    •  & Erik Ingelsson
  57. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

    • Talin Haritunians
  58. Centre for Population Health Sciences, The University of Edinburgh Medical School, Edinburgh EH16 4TJ, UK.

    • Lina Zgaga
    • , Sarah H. Wild
    • , Igor Rudan
    • , James F. Wilson
    •  & Harry Campbell
  59. Andrija Stampar School of Public Health, Medical School University of Zagreb, Zagreb, Croatia.

    • Lina Zgaga
  60. Faculty of Medicine, University of Split, Soltanska 2, 21000 Split, Croatia.

    • Ivana Kolcic
    • , Ozren Polasek
    • , Tatijana Zemunik
    •  & Igor Rudan
  61. Institute of Clinical Medicine, Department Of Internal Medicine, University of Oulu, 90014 Oulu, Finland.

    • M. Juhani Junttila
    •  & Heikki V. Huikuri
  62. Institut für Klinische Molekularbiologie, Christian-Albrechts Universität, 24098 Kiel, Germany.

    • Stefan Schreiber
  63. Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.

    • Annette Peters
  64. Munich Heart Alliance, 80802 Munich, Germany.

    • Annette Peters
  65. Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), 39100 Bolzano, Italy.

    • Andrew A. Hicks
  66. Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK.

    • Jonathan Stephens
    • , Nicola S. Foad
    •  & Jennifer D. Jolley
  67. NHS Blood and Transplant, Cambridge, Cambridge CB2 0PT, UK.

    • Jonathan Stephens
    • , Nicola S. Foad
    •  & Jennifer D. Jolley
  68. Finnish Institute of Occupational Health, 90220 Oulu, Finland.

    • Jaana Laitinen
  69. National Institute for Health and Welfare, 90101 Oulu, Finland.

    • Anneli Pouta
    •  & Marjo-Riitta Jarvelin
  70. Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, 90014 Oulu, Finland.

    • Anneli Pouta
  71. Institute of Health Sciences, Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.

    • Marika Kaakinen
    •  & Marjo-Riitta Jarvelin
  72. Department of Internal Medicine, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

    • Gerjan Navis
  73. Department of Cardiology, Division Heart & Lungs, University medical Center Utrecht, 3508 GA Utrecht, The Netherlands.

    • Folkert W. Asselbergs
  74. Institute of Epidemiology and Social Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.

    • Ulrich John
  75. Division of Research, Kaiser Permanente Northern California, Oakland, California 94612, USA.

    • Carlos Iribarren
  76. National Institutes on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Tamara Harris
    •  & Lenore Launer
  77. Human Genetics Center and Division of Epidemiology, The University of Texas Health Science Centers, Houston, Texas 77030, USA.

    • Eric Boerwinkle
  78. Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, Ontario M5G 1L7, Canada.

    • Gemma Cadby
    •  & Lyle J. Palmer
  79. Medicine and Pharmacology, University of Western Australia, Nedlands Western Australia 6009, Australia.

    • Alan L. James
    •  & Arthur W. Musk
  80. Pulmonary Physiology, Sir Charles Gairdner Hospital, University of Western Australia, Nedlands Western Australia 6009, Australia.

    • Alan L. James
  81. Respiratory Medicine, Sir Charles Gairdner Hospital, University of Western Australia, Nedlands Western Australia 6009, Australia.

    • Arthur W. Musk
  82. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, Washington 98101, USA.

    • Bruce M. Psaty
  83. Group Health Research Institute, Group Health Cooperative, Seattle, Washington 98101, USA.

    • Bruce M. Psaty
  84. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV) University Hospital, 1011 Lausanne, Switzerland.

    • Jacques S. Beckmann
  85. Department of Internal Medicine, University Hospital, 1011 Lausanne, Switzerland.

    • Gerard Waeber
    •  & Peter Vollenweider
  86. Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden.

    • Leif C. Groop
  87. Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.

    • Kay-Tee Khaw
  88. Division of Biostatistics, Washington University School of Medicine, St Louis, Missouri 63110, USA.

  89. Département de Médecine, Université de Montréal, Montréal, Québec H4J 1C5, Canada.

    • Jean-Claude Tardif
    •  & Guillaume Lettre
  90. Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.

    • Jean-Claude Tardif
    •  & Guillaume Lettre
  91. Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA.

    • L. Adrienne Cupples
    • , Caroline S. Fox
    •  & Sekar Kathiresan
  92. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Francis S. Collins
  93. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA.

    • Karen L. Mohlke
  94. Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Universität zu Lübeck, 23562 Lübeck, Germany.

    • Jeanette Erdmann
    •  & Heribert Schunkert
  95. Klinik und Poliklinik für Innere Medizin II, 93053 Regensburg, Germany.

    • Christian Hengstenberg
    •  & Klaus Stark
  96. Department of Cardiovascular Diseases, University of Leuven, 3000 Leuven, Belgium.

    • Jan A. Staessen
  97. Department of Epidemiology, Maastricht University, 6200 MD Maastricht, The Netherlands.

    • Jan A. Staessen
  98. Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), 39100 Bolzano, Italy.

    • Peter P. Pramstaller
  99. Department of Neurology, General Central Hospital, 39100 Bolzano, Italy.

    • Peter P. Pramstaller
  100. Department of Neurology, University of Lübeck, 23562 Lübeck, Germany.

    • Peter P. Pramstaller
  101. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.

    • Sekar Kathiresan
  102. Center for Human Genetics Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Sekar Kathiresan
  103. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Sekar Kathiresan
  104. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Sekar Kathiresan
  105. Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00014 Helsinki, Finland.

    • Samuli Ripatti
  106. Public Health Genomics Unit, National Institute for Health and Welfare, 00271 Helsinki, Finland.

    • Samuli Ripatti
  107. Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.

    • Samuli Ripatti
  108. Department of Epidemiology and Biostatistics, MRC-HPA Center for Environment and Health, Imperial College London, London W2 1PG, UK.

    • Marjo-Riitta Jarvelin
  109. Department of Psychiatry, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

    • Brenda Penninx
  110. Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20852, USA.

    • Stephen J. Chanock
    •  & Sonja I. Berndt
  111. Karolinska Institutet, 171 77 Stockholm, Sweden.

    • Anders Hamsten
  112. Atherosclerosis Research Unit, Department of Medicine, Solna, 171 76 Stockholm, Sweden.

    • Anders Hamsten
  113. Epidemiology, Biostatistics & HTA, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

    • Lambertus A. Kiemeney
    •  & Sita H. Vermeulen
  114. National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • David Schlessinger
  115. Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany.

    • Sabine Schipf
  116. Department of Medicine, University of Leipzig, 04103 Leipzig, Germany.

    • Michael Stumvoll
    •  & Anke Tönjes
  117. IFB Adiposity Diseases, University of Leipzig, 04103 Leipzig, Germany.

    • Michael Stumvoll
    •  & Anke Tönjes
  118. Department of Epidemiology and Carolina Center for Genome Sciences, The University of North Carolina, Chapel Hill, North Carolina 27514, USA.

    • Kari E. North
  119. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Old Road Headington, Oxford OX3 7LJ, UK.

    • Mark I. McCarthy
  120. Department of Psychiatry, Washington University St Louis, Missouri 63110, USA.

    • Andrew C. Heath
    •  & Pamela A. F. Madden
  121. Department of Biostatistics, University of Washington, Seattle, Washington 98115, USA.

    • Barbara McKnight
  122. Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 3JT, UK.

    • William G. Hill
  123. Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  124. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter EX1 2LU, UK.

    • Timothy M. Frayling
  125. Department of Food and Agricultural Systems, University of Melbourne, Victoria 3010, Australia.

    • Michael E. Goddard
  126. Biosciences Research Division, Department of Primary Industries, Bundoora, Victoria 3083, Australia.

    • Michael E. Goddard
  127. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia.

    • Peter M. Visscher

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Contributions

P.M.V., M.E.G. and J.Y. conceived and designed the study. J.Y. and P.M.V. derived the analytical theory. J.Y. performed the meta-analyses and simulations. J.Y. and P.M.V. wrote the first draft of the manuscript. J.Y., D.I.C., J.H.Z. and R.J.F.L. performed further statistical verification analyses. D.P.S., W.G.H., R.J.F.L., S.I.B. and H. Snieder contributed important additional concepts and critically reviewed the manuscript before submission. S.E.M., P.A.F.M., A.C.H., N.G.M., D.R.N. and G.W.M. contributed the individual-level genotype and phenotype data of the QIMR cohort. T.M.F., J.N.H. and R.J.F.L. liaised with the GIANT consortium for this project. The cohort-specific contributions of all other authors are provided in the Supplementary Information.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Peter M. Visscher.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Figures 1-10, Supplementary Tables 1-5, Supplementary Notes and Data, Supplementary References, Supplementary Acknowledgements (study-specific) and Supplementary Author Contributions. Supplementary Tables 4, 5 and the Acknowledgements were corrected on 31 January 2013.

About this article

Publication history

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DOI

https://doi.org/10.1038/nature11401

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