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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Human Genetics Open Access 14 June 2023
Nature Communications Open Access 06 July 2021
Transcriptome-wide association study uncovers the role of essential genes in anthracycline-induced cardiotoxicity
npj Genomic Medicine Open Access 21 May 2021
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Weedon, M.N. et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat. Genet. 39, 1245–1250 (2007).
Miyamoto, Y. et al. A functional polymorphism in the 5′ UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat. Genet. 39, 529–533 (2007).
Silventoinen, K. et al. Heritability of adult body height: a comparative study of twin cohorts in eight countries. Twin Res. 6, 399–408 (2003).
Pilia, G. et al. Heritability of cardiovascular and personality traits in 6,148 Sardinians. PLoS Genet. 2, e132 (2006).
Perola, M. et al. Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci. PLoS Genet. 3, e97 (2007).
Scott, L.J. et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 1341–1345 (2007).
Scuteri, A. et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 3, e115 (2007).
Chen, W.M. & Abecasis, G.R. Family based association tests for genome wide association scans. Am. J. Hum. Genet. 81, 913–926 (2007).
Vetter, K. & Wurst, W. Expression of a novel mouse gene 'mbFZb' in distinct regions of the developing nervous system and the adult brain. Mech. Dev. 100, 123–125 (2001).
Valdes, A.M. et al. Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis Rheum. 56, 137–146 (2007).
Imabayashi, H. et al. Redifferentiation of dedifferentiated chondrocytes and chondrogenesis of human bone marrow stromal cells via chondrosphere formation with expression profiling by large-scale cDNA analysis. Exp. Cell Res. 288, 35–50 (2003).
Goldring, M.B., Tsuchimochi, K. & Ijiri, K. The control of chondrogenesis. J. Cell. Biochem. 97, 33–44 (2006).
Chang, S.C. et al. Cartilage-derived morphogenetic proteins. New members of the transforming growth factor-β superfamily predominantly expressed in long bones during human embryonic development. J. Biol. Chem. 269, 28227–28234 (1994).
Chujo, T. et al. Effects of growth differentiation factor-5 on the intervertebral disc—in vitro bovine study and in vivo rabbit disc degeneration model study. Spine 31, 2909–2917 (2006).
Voight, B.F., Kudaravalli, S., Wen, X. & Pritchard, J.K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).
Southam, L. et al. An SNP in the 5′-UTR of GDF5 is associated with osteoarthritis susceptibility in Europeans and with in vivo differences in allelic expression in articular cartilage. Hum. Mol. Genet. 16, 2226–2232 (2007).
McKenzie, C.A. et al. Trans-ethnic fine mapping of a quantitative trait locus for circulating angiotensin I–converting enzyme (ACE). Hum. Mol. Genet. 10, 1077–1084 (2001).
Frere, C. et al. Fine mapping of quantitative trait nucleotides underlying thrombin-activatable fibrinolysis inhibitor antigen levels by a transethnic study. Blood 108, 1562–1568 (2006).
Skol, A.D., Scott, L.J., Abecasis, G.R. & Boehnke, M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).
Burdick, J.T., Chen, W.M., Abecasis, G.R. & Cheung, V.G. In silico method for inferring genotypes in pedigrees. Nat. Genet. 38, 1002–1004 (2006).
Diabetes Genetics Initiative. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316, 1331–1336 (2007).
Hsueh, W.C. et al. Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study. Diabetes Care 23, 595–601 (2000).
Streeten, E.A. et al. Reduced incidence of hip fracture in the Old Order Amish. J. Bone Miner. Res. 19, 308–313 (2004).
ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. Am. J. Epidemiol. 129, 687–702 (1989).
The Caerphilly and Speedwell Collaborative Group. Caerphilly and Speedwell collaborative heart disease studies. J. Epidemiol. Community Health 38, 259–262 (1984).
Fehily, A.M., Butland, B.K. & Yarnell, J.W. Body fatness and frame size: the Caerphilly study. Eur. J. Clin. Nutr. 44, 107–111 (1990).
Lawlor, D.A., Bedford, C., Taylor, M. & Ebrahim, S. Geographical variation in cardiovascular disease, risk factors, and their control in older women: British Women's Heart and Health Study. J. Epidemiol. Community Health 57, 134–140 (2003).
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
The International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
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).
About this article
Cite this article
Sanna, S., Jackson, A., Nagaraja, R. et al. Common variants in the GDF5-UQCC region are associated with variation in human height. Nat Genet 40, 198–203 (2008). https://doi.org/10.1038/ng.74
This article is cited by
Human Genetics (2023)
Nature Genetics (2022)
Non-invasive evaluation of NAFLD and the contribution of genes: an MRI-PDFF-based cross-sectional study
Hepatology International (2022)
Nature Genetics (2022)
Genome Biology (2021)