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Identification of ten loci associated with height highlights new biological pathways in human growth

Nature Genetics volume 40, pages 584–591 (2008)Cite this article

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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Figure 1: Quantile-quantile plot of ∼2.2 million SNPs for each of the six genome-wide association scans meta-analyzed.
Figure 2: Quantile-quantile plots supporting the presence of additional loci associated with height.
Figure 3: Analysis of combined effects.

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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

  1. , , , , and: A full list of authors and affiliations appears in the Supplementary Note online.

  2. Anne U Jackson, Christian Gieger, Fredrick R Schumacher, Sonja I Berndt and Serena Sanna: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, 02142, Massachusetts, 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, 02115, Massachusetts, USA

    Guillaume Lettre, Johannah L Butler & Joel N Hirschhorn

  3. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Anne U Jackson, Serena Sanna, Michael Boehnke & Gonçalo R Abecasis

  4. Institute of Epidemiology, GSF National Research Center for Environment and Health, Neuherberg, 85764, 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, Munich, 81377, Germany

    Christian Gieger, Susana Eyheramendy, Iris M Heid & H-Erich Wichmann

  6. Department of Medicine, Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Fredrick R Schumacher, Frank B Hu & David J Hunter

  7. Department of Epidemiology, Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA

    Fredrick R Schumacher, Frank B Hu, Peter Kraft & David J Hunter

  8. Division of Cancer Epidemiology and Genetics, Department of Health and Human Services (DHHS), Occupational and Environmental Epidemiology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, 20892, Maryland, 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, 09042, Cagliari, Italy

    Serena Sanna & Manuela Uda

  10. Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Benjamin F Voight

  11. Bioinformed Consulting Services, Gaithersburg, 20877, Maryland, USA

    Kevin B Jacobs

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

    Valeriya Lyssenko & Leif C Groop

  13. Division of Cancer Epidemiology and Genetics, Laboratory of Translational Genomics, NCI, NIH, DHHS, Bethesda, 20892, Maryland, 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, Helsinki, FI-00014, Finland

    Leena Peltonen

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

    Veikko Salomaa

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

    David Schlessinger

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

    Karen L Mohlke

  23. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Joel N Hirschhorn

Authors
  1. Guillaume Lettre
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Consortia

The Diabetes Genetics Initiative

FUSION

KORA

The Prostate, Lung Colorectal and Ovarian Cancer Screening Trial

The Nurses' Health Study

SardiNIA

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 Methods, Supplementary Tables 1–9, Supplementary Note, Supplementary Figures 1 and 2 (PDF 1478 kb)

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Lettre, G., Jackson, A., Gieger, C. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet 40, 584–591 (2008). https://doi.org/10.1038/ng.125

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