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Genome-wide association analysis identifies 20 loci that influence adult height

Nature Genetics volume 40, pages 575–583 (2008)Cite this article

Abstract

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 × 10−7, with 10 reaching P < 1 × 10−10). Combined, the 20 SNPs explain ∼3% of height variation, with a ∼5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.

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Figure 1: Quantile-quantile plots for the 402,951 SNPs from the genome-wide association meta-analysis as more studies are added in.
Figure 2: Manhattan plot for the 402,951 SNPs from the stage 1 genome-wide association meta-analysis of the WTCCC-T2D, DGI, WTCCC-HT, WTCCC-CAD, EPIC-Obesity and WTCCC-UKBS studies.
Figure 3: The combined impact of the 20 SNPs with a P < 5 × 10−7.
Figure 4: Power estimates.
Figure 5: Comparison of results across independent meta-analyses.

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Acknowledgements

M.N.W. is a Vandervell Foundation Research Fellow. C.L. is a Nuffield Department of Medicine Scientific Leadership Fellow. R.M.F. is funded by a Diabetes UK research studentship. S.B. is supported by the Giorgi-Cavaglieri Foundation and the Swiss National Science Foundation (grant 3100AO-116323/1), which also supports J.S.B. (grant 310000-112552/1). We would like to thank M. Bochud, Z. Kutalik, G. Waeber, K. Song and X. Yuan for their contribution to the Lausanne study. The WTCCC CAD cohort collection was supported by grants from the British Heart Foundation, Medical Research Council and National Health Service Research & Development. N.J.S. holds a chair supported by the British Heart Foundation. We thank the Wellcome Trust for funding. C.W. is funded by the British Heart Foundation (grant number FS/05/061/19501). The BRIGHT study is supported by the Medical Research Council (grant number G9521010D) and the British Heart Foundation (grant number PG02/128).

Author information

Author notes

  1. Michael N Weedon, Hana Lango, Jing Hua Zhao, Shengxu Li, Ruth J F Loos and Nicholas J Wareham: These authors contributed equally to this work.

Authors and Affiliations

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

    Michael N Weedon, Hana Lango, Rachel M Freathy, John R B Perry, 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, Hana Lango, Rachel M Freathy, John R B Perry, Beverly Shields, Andrew T Hattersley & Timothy M Frayling

  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK

    Cecilia M Lindgren, Inga Prokopenko & Mark I McCarthy

  4. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK

    Cecilia M Lindgren, Inga Prokopenko & Mark I McCarthy

  5. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine, Charterhouse Square, London, EC1M 6BQ, UK

    Chris Wallace, Mark Caulfield & Patricia B Munroe

  6. Department of Social Medicine, Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, BS8 2PR, UK

    David M Evans

  7. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK

    Massimo Mangino, Suzanne Stevens & Nilesh J Samani

  8. Leeds Institute of Genetics Health and Therapeutics, Faculty of Medicine and Health, University of Leeds, Leeds, LS2 9JT, UK

    Alistair S Hall

  9. Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK

    Martin Farrall

  10. British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK

    Anna Dominiczak

  11. Department of Medical Genetics, University of Lausanne, Lausanne, 1011, Switzerland

    Toby Johnson, Sven Bergmann & Jacques S Beckmann

  12. Swiss Institute of Bioinformatics, Lausanne, 1015, Switzerland

    Toby Johnson & Sven Bergmann

  13. Institut Universitaire de Médecine Sociale et Préventive, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland

    Toby Johnson

  14. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland

    Jacques S Beckmann

  15. Department of Medicine, Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland

    Peter Vollenweider

  16. Medical Genetics/Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, King of Prussia, 19406, Pennsylvania, USA

    Dawn M Waterworth & Vincent Mooser

  17. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK

    Colin N A Palmer

  18. Division of Medicine and Therapeutics, Diabetes Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK

    Andrew D Morris

  19. Department of Haematology, University of Cambridge, Long Road, Cambridge, CB2 2BT, UK

    Willem H Ouwehand

  20. National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge, CB2 2BT, UK

    Willem H Ouwehand

  21. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK

    Jing Hua Zhao, Shengxu Li, Ruth J F Loos & Nicholas J Wareham

  22. Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK

    Inês Barroso, Panagiotis Deloukas, Eleanor Wheeler, Nicole Soranzo & Michael Inouye

  23. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, CB2 2SR, UK

    Manjinder S Sandhu

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  1. Michael N Weedon
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Consortia

Diabetes Genetics Initiative

The Wellcome Trust Case Control Consortium

Cambridge GEM Consortium

  • Jing Hua Zhao
  • , Shengxu Li
  • , Ruth J F Loos
  • , Inês Barroso
  • , Panagiotis Deloukas
  • , Manjinder S Sandhu
  • , Eleanor Wheeler
  • , Nicole Soranzo
  • , Michael Inouye
  •  & Nicholas J Wareham

Contributions

M.N.W., H.L., C.M.L., C.W., D.M.E., M.M., J.R.B.P., S.S., I.P., members of the DGI, WTCCC, the GEM consortium, S.B., T.J. and D.M.W. were responsible for analyzing, quality control checking and cleaning the data from the individual GWA studies. C.W., R.M.F., B.S., M.N.W. and H.L. were responsible for analysis of the stage 2 samples. M.N.W. performed the meta-analyses. A.S.H. and N.J.S. are principal investigators from the WTCCC-CAD study. M.C. and M.F. are principal investigators from the WTCCC-HT study. W.H.O. is principal investigator of the WTCCC-UKBS study. A.T.H. and M.I.M. are principal investigators for the WTCCC-T2D study. J.S.B., P.V. and V.M. are principal investigators of the CoLaus study. M.C., M.F., A.D. and P.B.M. are principal investigators on the BRIGHT study. A.T.H. is principal investigator of the EFSOCH study. C.N.A.P. and A.D.M. are principal investigators of the Tayside UKT2D-GCC study. M.N.W., H.L., A.T.H., M.I.M. and T.M.F. wrote the manuscript. A.T.H., M.I.M., M.N.W. and T.M.F. designed and led the study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Timothy M Frayling.

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A full list of authors is provided in the Supplementary Note

A full list of authors is provided in the Supplementary Note

A full list of authors and affiliations appears at the end of this paper.

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Supplementary Tables 1–5, Supplementary Figures 1–3, Supplementary Note (PDF 4393 kb)

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Weedon, M., Lango, H., Lindgren, C. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nat Genet 40, 575–583 (2008). https://doi.org/10.1038/ng.121

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