Abstract

Identifying genetic variants that influence human height will advance our understanding of skeletal growth and development. Several rare genetic variants have been convincingly and reproducibly associated with height in mendelian syndromes, and common variants in the transcription factor gene HMGA2 are associated with variation in height in the general population1. Here we report genome-wide association analyses, using genotyped and imputed markers, of 6,669 individuals from Finland and Sardinia, and follow-up analyses in an additional 28,801 individuals. We show that common variants in the osteoarthritis-associated locus2 GDF5-UQCC contribute to variation in height with an estimated additive effect of 0.44 cm (overall P < 10−15). Our results indicate that there may be a link between the genetic basis of height and osteoarthritis, potentially mediated through alterations in bone growth and development.

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Acknowledgements

We thank the individuals who participated in this study; Y. Li for computational analysis; K. Gaulton, A. Swift, M. Erdos and N. Narisu for FUSION genotyping and technical expertise; investigators at the Center for Inherited Disease Research for FUSION GWAS genotyping; staff and participants of the ARIC study for contributions; and the Amish Research Clinic Staff for study subject recruitment and characterization. The SardiNIA team thanks Monsignore Piseddu (Bishop of Ogliastra), the mayors and citizens of the four Sardinian towns (Lanusei, Ilbono, Arzana and Elini), and the head of the Public Health Unit ASL4 for cooperation; A. Maschio, F. Busonero, A. Mulas, N. Sestu and M. Grazia Piras for genotyping and technical expertise; and all of the physicians, nurses and recruitment personnel of the ProgeNIA group in Lanusei. This research was supported (in part) by the intramural Research Program of the US National Institutes of Health (NIH) National Institute on Aging (contracts NO1-AG-1-2109 to the SardiNIA ('Progenia') team and 263-MA-410953 to the University of Michigan (G.R.A.)); NIH grants DK072193 (K.L.M.), HL084729 (G.R.A.), HG002651 (G.R.A.), DK062370 (M.B.), DK54361 (A.R.S.), HL72515 (A.R.S.), AG18728 (A.R.S.) and AR046838 (A.R.S.); the National Human Genome Research Institute (intramural project number 1 Z01 HG000024 (F.S.C.)); the American Diabetes Association, including a postdoctoral fellowship award (C.J.W.); and March of Dimes (research grant 6-FY04-61 (J.N.H.)). K.L.M. and G.R.A are Pew Scholars in the Biomedical Sciences. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute (contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021 and N01-HC-55022). FUSION GWAS genotyping was performed with support from CIDR NIH (contract N01-HG-65403) and the John Hopkins University Genetic Resources Core Facility SNP Center. The whole-genome genotyping and analysis in the Diabetic Genetics Initiative genome scan 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). Funding and support were also provided by the University of Maryland General Clinical Research Center (M01 RR 16500), the National Institute of Diabetes and Digestive and Kidney Diseases Clinical Nutrition Research Unit of Maryland (NIH P30 DK072488), the Department of Veterans Affairs, and Veterans Affairs Medical Center Baltimore Geriatric Research, Education and Clinical Center. The Caerphilly study was funded by the UK MRC. The Caerphilly study was undertaken by the former MRC Epidemiology Unit in South Wales and was funded by the UK MRC. The data archive is maintained by the Department of Social Medicine, University of Bristol. We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the MRC (grant G0000934) and the Wellcome Trust (grant 068545/Z/02).

Author information

Author notes

    • Serena Sanna
    •  & Anne U Jackson

    These authors contributed equally to this work.

Affiliations

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

    • Serena Sanna
    • , Anne U Jackson
    • , Cristen J Willer
    • , Wei-Min Chen
    • , Heather M Stringham
    • , Laura J Scott
    • , Michael Boehnke
    •  & Gonçalo R Abecasis
  2. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.

    • Serena Sanna
    • , Gianluca Usala
    • , Mariano Dei
    • , Sandra Lai
    • , Giuseppe Albai
    • , Laura Crisponi
    • , Silvia Naitza
    • , Manuela Uda
    •  & Antonio Cao
  3. Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.

    • Ramaiah Nagaraja
    •  & David Schlessinger
  4. Division of Biostatistics and Epidemiology, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.

    • Wei-Min Chen
  5. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

    • Lori L Bonnycastle
    • , Peter S Chines
    •  & Francis S Collins
  6. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    • Haiqing Shen
    •  & Alan R Shuldiner
  7. Department of Social Medicine, University of Bristol, Canynge Hall, Bristol BS8 2PR, UK.

    • Nicholas Timpson
    • , Yoav Ben-Shlomo
    • , Debbie A Lawlor
    •  & George Davey Smith
  8. Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Canynge Hall, Bristol BS8 2PR, UK.

    • Nicholas Timpson
    • , Debbie A Lawlor
    •  & George Davey Smith
  9. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA.

    • Guillaume Lettre
    •  & Joel N Hirschhorn
  10. Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224, USA.

    • Kimberly F Doheny
    •  & Elizabeth W Pugh
  11. London School of Hygiene and Tropical Medicine, University of London, London WC1E 7HT, UK.

    • Shah Ebrahim
  12. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Richard N Bergman
    •  & Richard M Watanabe
  13. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.

    • Richard M Watanabe
  14. Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, 00300 Helsinki, and Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.

    • Jaakko Tuomilehto
  15. Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.

    • Josef Coresh
  16. Geriatric Research and Education Center, Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.

    • Alan R Shuldiner
  17. Human Genetics Center and Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas 77225, USA.

    • Eric Boerwinkle
  18. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Karen L Mohlke

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Contributions

D.S., F.S.C., A.C., M.B., G.R.A. and K.L.M. designed the study; Y.B.-S., S.E., D.A.L., J.T., J.C., J.N.H., A.R.S., D.S., G.D.S., E.B. and A.C. provided material and reagents; R.N., L.L.B., G.U., P.S.C., M.D., S.L., L.C., S.N., K.F.D., E.W.P., R.N.B., R.M.W. and M.U. performed the research; S.S., A.U.J., C.J.W., W.-M.C., H.S., N.T., G.L., H.M.S., L.J.S., G.A., M.B. and G.R.A. analyzed the data; and S.S., A.U.J., C.J.W., A.C., M.B., G.R.A. and K.L.M. wrote the paper.

Corresponding authors

Correspondence to Gonçalo R Abecasis or Karen L Mohlke.

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    Supplementary Methods, Supplementary Tables 1–5, Supplementary Figures 1 and 2

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DOI

https://doi.org/10.1038/ng.74

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