Abstract

Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 × 10−7 to 8 × 10−22). Together, these 12 loci account for 2% of the population variation in height. Individuals with ≤8 height-increasing alleles and ≥16 height-increasing alleles differ in height by 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait.

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Acknowledgements

We thank members of our laboratories for helpful discussion, and gratefully acknowledge all of the participants in the studies. Contributing members for the DGI, FUSION, KORA and SardiNIA GWA scans are listed in the Supplementary Note. The authors acknowledge C. Chen of Bioinformed Consulting Services Inc. for expert programming, and L. Qi for his assistance. The authors thank C. Berg and P. Prorok, Division of Cancer Prevention, National Cancer Institute, the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, T. Riley and staff, Information Management Services, Inc., and B. O'Brien and staff, Westat, Inc. KORA gratefully acknowledges the contribution of T. Meitinger and all other members of the GSF genotyping staff in generating the SNP dataset. We thank the Mayor and the administration in Lanusei for providing and furnishing the clinic site; and the mayors of Ilbono, Arzana and Elini, the head of the local Public Health Unit ASL4. Support for this work was provided by the following: US National Institutes of Health grants 5P01CA087969 and CA49449 (S.E. Hankinson), 5UO1CA098233 (D.J.H.), DK62370 (M.B.), DK72193 (K.L.M.), HG02651 and HL084729 (G.R.A.); Novartis Institutes for BioMedical Research (D. Altshuler); March of Dimes grant 6-FY04-61 (J.N.H.); EU Projects GenomEUtwin grant QLG2-CT-2002-01254 and the Center of Excellence in Complex Disease Genetics of the Academy of Finland (L.P.); the Sigrid Juselius Foundation (L.C.G., V.S. and PPP); the Finnish Diabetes Research Foundation and the Folkhälsan Research Foundation and Clinical Research Institute HUCH (L.C.G.); this research was supported (in part) by the intramural Research Program of the NIH, National Institute on Aging; the PLCO research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; KORA/MONICA Augsburg studies were financed by the GSF-National Research Center for Environment and Health, Munich/Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF); part of this work by KORA was supported by the German National Genome Research Network (NGFN), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and a subcontract of the 5 R01 DK 075787 by the NIH/NIDDK to the GSF-National Research Center for Environment and Health (to J.N.H.).

Author information

Author notes

    • Anne U Jackson
    • , Christian Gieger
    • , Fredrick R Schumacher
    • , Sonja I Berndt
    •  & Serena Sanna

    These authors contributed equally to this work.

Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

    • Guillaume Lettre
    • , Benjamin F Voight
    • , Candace Guiducci
    • , Rachel Hackett
    • , Leena Peltonen
    • , David J Hunter
    •  & Joel N Hirschhorn
  2. Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, Massachusetts 02115, USA.

    • Guillaume Lettre
    • , Johannah L Butler
    •  & Joel N Hirschhorn
  3. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Anne U Jackson
    • , Serena Sanna
    • , Michael Boehnke
    •  & Gonçalo R Abecasis
  4. Institute of Epidemiology, GSF National Research Center for Environment and Health, 85764 Neuherberg, Germany.

    • Christian Gieger
    • , Susana Eyheramendy
    • , Thomas Illig
    • , Iris M Heid
    •  & H-Erich Wichmann
  5. Department of Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, University of Munich, 81377 Munich, Germany.

    • Christian Gieger
    • , Susana Eyheramendy
    • , Iris M Heid
    •  & H-Erich Wichmann
  6. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Fredrick R Schumacher
    • , Frank B Hu
    •  & David J Hunter
  7. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Fredrick R Schumacher
    • , Frank B Hu
    • , Peter Kraft
    •  & David J Hunter
  8. Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland 20892, USA.

    • Sonja I Berndt
    •  & Richard B Hayes
  9. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.

    • Serena Sanna
    •  & Manuela Uda
  10. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Benjamin F Voight
  11. Bioinformed Consulting Services, Gaithersburg, Maryland 20877, USA.

    • Kevin B Jacobs
  12. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, 205 02 Malmö, Sweden.

    • Valeriya Lyssenko
    •  & Leif C Groop
  13. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, Maryland 20892, USA.

    • Stephen J Chanock
  14. Department of Medicine, Helsinki University Central Hospital, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland.

    • Leif C Groop
  15. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Frank B Hu
    •  & David J Hunter
  16. Malmska Municipal Health Center and Hospital, Jakobstad, Finland.

    • Bo Isomaa
  17. Folkhälsan Research Center, Helsinki, Finland.

    • Bo Isomaa
  18. Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.

    • Leena Peltonen
  19. Department of Molecular Medicine, National Public Health Institute and Department of Medical Genetics, University of Helsinki, FI-00014 Helsinki, Finland.

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

    • Veikko Salomaa
  21. Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.

    • David Schlessinger
  22. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Karen L Mohlke
  23. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Joel N Hirschhorn

Consortia

  1. The Diabetes Genetics Initiative

  2. FUSION

  3. KORA

  4. The Prostate, Lung Colorectal and Ovarian Cancer Screening Trial

  5. The Nurses' Health Study

  6. SardiNIA

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Contributions

G.L., A.U.J., C. Gieger., F.R.S., S.I.B., S.S., S.E. and B.F.V. performed analyses. G.L. performed the meta-analysis and selected markers for follow-up. J.L.B., C. Guiducci, T.I. and R.H. genotyped markers in some of the follow-up panels. G.L. and J.N.H. wrote the manuscript, with inputs from the other authors, especially M.B. and S.I.B. V.L., L.C.G., B.I. and J.N.H. are investigators of the DGI and Botnia studies. L.P. and V.S. are investigators of the FINRISK97 study. M.U., D.S. and G.R.A. are investigators of the SardiNIA study. K.B.J., S.J.C. and R.B.H. are investigators of the PLCO study. I.M.H. and H.-E.W. are investigators of the KORA study. M.B. and K.L.M. are investigators of the FUSION study. F.B.H., P.K. and D.J.H. are investigators of the NHS. D.J.H, R.B.H., G.R.A., H.-E.W., K.L.M. and J.N.H. led this study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Joel N Hirschhorn.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Methods, Supplementary Tables 1–9, Supplementary Note, Supplementary Figures 1 and 2

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DOI

https://doi.org/10.1038/ng.125

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