Article abstract

Nature Genetics 40, 584 - 591 (2008)
Published online: 6 April 2008 | doi:10.1038/ng.125

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

Guillaume Lettre1,2, Anne U Jackson3,25, Christian Gieger4,5,25, Fredrick R Schumacher6,7,25, Sonja I Berndt8,25, Serena Sanna3,9,25, Susana Eyheramendy4,5, Benjamin F Voight1,10, Johannah L Butler2, Candace Guiducci1, Thomas Illig4, Rachel Hackett1, Iris M Heid4,5, Kevin B Jacobs11, Valeriya Lyssenko12, Manuela Uda9, The Diabetes Genetics Initiative24, FUSION24, KORA24, The Prostate, Lung Colorectal and Ovarian Cancer Screening Trial24, The Nurses' Health Study24, SardiNIA24, Michael Boehnke3, Stephen J Chanock13, Leif C Groop12,14, Frank B Hu6,7,15, Bo Isomaa16,17, Peter Kraft7, Leena Peltonen1,18,19, Veikko Salomaa20, David Schlessinger21, David J Hunter1,6,7,15, Richard B Hayes8, Gonçalo R Abecasis3, H-Erich Wichmann4,5, Karen L Mohlke22 & Joel N Hirschhorn1,2,23

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 times 10- 7 to 8 times 10- 22). Together, these 12 loci account for approx2% of the population variation in height. Individuals with less than or equal to8 height-increasing alleles and greater than or equal to16 height-increasing alleles differ in height by approx3.5 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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  1. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
  2. Divisions of Genetics and Endocrinology and Program in Genomics, Children's Hospital, Boston, Massachusetts 02115, USA.
  3. Center for Statistical Genetics, Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA.
  4. Institute of Epidemiology, GSF National Research Center for Environment and Health, 85764 Neuherberg, Germany.
  5. Department of Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, University of Munich, 81377 Munich, Germany.
  6. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
  7. Program in Molecular and Genetic Epidemiology, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.
  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.
  9. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  10. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  11. Bioinformed Consulting Services, Gaithersburg, Maryland 20877, USA.
  12. Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, 205 02 Malmö, Sweden.
  13. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, Maryland 20892, USA.
  14. Department of Medicine, Helsinki University Central Hospital, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland.
  15. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
  16. Malmska Municipal Health Center and Hospital, Jakobstad, Finland.
  17. Folkhälsan Research Center, Helsinki, Finland.
  18. Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
  19. Department of Molecular Medicine, National Public Health Institute and Department of Medical Genetics, University of Helsinki, FI-00014 Helsinki, Finland.
  20. Department of Epidemiology and Health Promotion. National Public Health Institute, FI-00300 Helsinki, Finland.
  21. Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA.
  22. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
  23. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
  24. A full list of authors and affiliations appears in the Supplementary Note online.
  25. These authors contributed equally to this work.

Correspondence to: Joel N Hirschhorn1,2,23 e-mail: joelh@broad.mit.edu



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