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Abstract

Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10−8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10−11, overall P = 4 × 10−16, including the genome-wide association data). We also observed the association in children (P = 1 × 10−6, N = 6,827) and a tall/short case-control study (P = 4 × 10−6, N = 3,207). We estimate that rs1042725 explains 0.3% of population variation in height (0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.

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Acknowledgements

For the UK-based studies, collection of the type 2 diabetes cases was supported by Diabetes UK, BDA Research and the UK Medical Research Council (MRC) (Biomedical Collections Strategic Grant G0000649). The UK Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). The ALSPAC study was supported by The UK MRC, the Wellcome Trust and the University of Bristol. The Exeter Family Study of Childhood Health was supported by UK National Health Service Research and Development and the Wellcome Trust. We also thank the Exeter University Foundation for funding. The UK GWA genotyping was supported by the Wellcome Trust (076113), and replication genotyping was supported by the Wellcome Trust, Diabetes UK, European Commission (EURODIA LSHG-CT-2004-518153) and the Peninsula Medical School. Personal funding comes from the Wellcome Trust (A.T.H.; Research Leave Fellow; Research Career Development Fellow); UK MRC (J.R.B.P.); Diabetes UK (R.M.F.) and the Throne-Holst Foundation (C.M.L.). M.N.W. is Vandervell Foundation Research Fellow at the Peninsula Medical School. C.M.L. is a University of Oxford Nuffield Department of Medicine Scientific Leader Fellow. C.N.A.P. and A.D.M. are supported by the Scottish executive as part of the Generation Scotland Initiative. We acknowledge the assistance of many colleagues involved in sample collection, phenotyping and DNA extraction in all the different studies. We thank K. Parnell, C. Kimber, A. Murray and K. Northstone for technical assistance. We thank S. Howell, M. Murphy and A. Wilson (Diabetes UK) for their long-term support for these studies. We also acknowledge the efforts of J. Collier, P. Robinson, S. Asquith and others at KBiosciences for their rapid and accurate large-scale genotyping. Finally, we acknowledge all participants in the various studies.

For the studies using the Scandinavian, US and Polish samples, the work was supported by a March of Dimes grant (#6-FY04-61) to J.N.H. and by a grant from The Center of Excellence in Complex Disease Genetics of the Academy of Finland (EU Projects GenomEUtwin, QLG2-CT-2002-01254) (L.P.). The FINRISK study was supported by the Sigrid Juselius Foundation. We thank members of our laboratories and of the Altshuler and Daly laboratories for helpful discussion, and we gratefully acknowledge all of the participants in the studies. We also thank J. Butler for excellent technical assistance and M. Kuokkanen for logistical help with the FINRISK97 cohort.

The whole-genome genotyping and analysis in the DGI genome scan (see Supplementary Note online for contributors) was supported by Novartis Institutes for BioMedical Research (to D. Altshuler), with additional support from The Richard and Susan Smith Family Foundation/American Diabetes Association Pinnacle Program Project Award (to D. Altshuler, J.N.H. and M.J. Daly). R.S. is supported by a US National Institutes of Health (NIH) Research Service Award. G.L. is supported by a March of Dimes research grant (6-FY04-61). Members of the DGI study group acknowledge support from an NIH/National Heart, Lung, and Blood Institute grant (U01 HG004171), the Burroughs Wellcome Fund and the Doris Duke Charitable Foundation. L.C.G. and members of the Botnia Study were funded by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, the Folkhalsan Research Foundation and Clinical Research Institute HUCH. The Malmö Study was funded by a Linné grant from the Swedish Research Council. L.C.G. is supported principally by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH. Work in Malmö, Sweden was also funded by a Linné grant from the Swedish Research Council. We thank the Botnia and Skara research teams for clinical contributions, and colleagues at Massachusetts General Hospital, Harvard, Broad and Novartis for discussions.

Author information

Author notes

    • Michael N Weedon
    • , Guillaume Lettre
    • , Rachel M Freathy
    • , Cecilia M Lindgren
    • , Mark I McCarthy
    • , Joel N Hirschhorn
    •  & Timothy M Frayling

    These authors contributed equally to this work.

Affiliations

  1. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.

    • Michael N Weedon
    • , Rachel M Freathy
    • , John R B Perry
    • , Hana Lango
    • , Andrew T Hattersley
    •  & Timothy M Frayling
  2. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.

    • Michael N Weedon
    • , Rachel M Freathy
    • , John R B Perry
    • , Beverley Shields
    • , Hana Lango
    • , Andrew T Hattersley
    •  & Timothy M Frayling
  3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Guillaume Lettre
    • , Benjamin F Voight
    • , Rachel Hackett
    • , Candace Guiducci
    • , Noel P Burtt
    • , Richa Saxena
    • , Kristin Ardlie
    • , Leena Peltonen
    •  & Joel N Hirschhorn
  4. Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, Massachusetts 02115, USA.

    • Guillaume Lettre
    •  & Joel N Hirschhorn
  5. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Cecilia M Lindgren
    • , Katherine S Elliott
    • , Eleftheria Zeggini
    • , Nicholas J Timpson
    •  & Mark I McCarthy
  6. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Cecilia M Lindgren
    • , Nigel W Rayner
    •  & Mark I McCarthy
  7. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Benjamin F Voight
    •  & Richa Saxena
  8. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, 205 02 Malmö, Sweden.

    • Valeriya Lyssenko
    •  & Leif C Groop
  9. Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland.

    • Valeriya Lyssenko
    •  & Leif C Groop
  10. The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK.

    • Nicholas J Timpson
    •  & George Davey Smith
  11. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Richa Saxena
  12. Clinical Science at South Bristol, University of Bristol, Bristol BS2 8AE, UK.

    • Jonathan H Tobias
  13. Department of Oral and Dental Science, Bristol Dental School, University of Bristol, Lower Maudlin Street, Bristol BS1 2LY, UK.

    • Andrew R Ness
  14. Department of Social Medicine, University of Bristol, Canynge Hall, Whiteladies Road, Bristol BS8 2PR, UK.

    • Susan M Ring
  15. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

    • Colin N A Palmer
  16. Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK.

    • Andrew D Morris
  17. Department of Molecular Medicine, National Public Health Institute, Biomedicum, FI-00290 Helsinki, Finland.

    • Leena Peltonen
  18. Department of Medical Genetics, University of Helsinki, FI-00014 Helsinki, Finland.

    • Leena Peltonen
  19. Department of Epidemiology and Health Promotion, National Public Health Institute, FI-00300 Helsinki, Finland.

    • Veikko Salomaa
  20. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Joel N Hirschhorn

Consortia

  1. The Diabetes Genetics Initiative

  2. The Wellcome Trust Case Control Consortium

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Contributions

Members of the WTCCC and DGI are listed in the Supplementary Note. M.N.W., G.L., R.M.F. and C.M.L. performed the analyses and wrote the first draft of the paper. J.R.B.P., K.S.E., B.S., E.Z., H.L., N.J.T. and N.W.R. were responsible for production, quality control and cleaning of the GWA data from the WTCCC samples. B.F.V., C.G., V.L., N.P.B. and R.S. were responsible for the production, quality control checking and cleaning of the GWA data from the DGI samples. B.F.V. also performed association testing and EIGENSTRAT analyses for height on the DGI data set. S.M.R. performed the data linking and quality control analysis for the ALSPAC study. R.H. and C.G. genotyped rs1042725 in the FINRISK97 cohort. K.A. is principal investigator for the near-extreme height panel. L.P. and V.S. are principal investigators for FINRISK97. L.C.G. is principal investigator for the Botnia study. G.D.S. is principal investigator of the ALSPAC study. J.H.T. and A.R.N. generated DXA measures in the ALSPAC children. C.N.A.P. and A.D.M. are principal investigators of the Tayside UKT2D-GCC study. A.T.H., M.I.M., J.N.H. and T.M.F. designed and led the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Timothy M Frayling.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–6, Supplementary Methods, Supplementary Note

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DOI

https://doi.org/10.1038/ng2121

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