Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Abstract

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Phenotypic variance explained by common variants.
Figure 2: Example of a locus with a secondary signal before (a) and after (b) conditioning.
Figure 3: Loci associated with height contain genes related to each other.

References

  1. Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009)

    Article  ADS  CAS  Google Scholar 

  2. Galton, F. Regression towards mediocrity in hereditary stature. J. R. Anthropol. Inst. 5, 329–348 (1885)

    Google Scholar 

  3. Fisher, R. A. The correlation between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinb. 52, 399–433 (1918)

    Article  Google Scholar 

  4. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007)

    Article  ADS  CAS  Google Scholar 

  5. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999)

    Article  CAS  Google Scholar 

  6. Reich, D. E. & Goldstein, D. B. Detecting association in a case-control study while correcting for population stratification. 20, 4–16 (2001)

  7. Campbell, C. D. et al. Demonstrating stratification in a European American population. Nature Genet. 37, 868–872 (2005)

    Article  CAS  Google Scholar 

  8. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009)

    Article  ADS  CAS  Google Scholar 

  9. Visscher, P. M. et al. Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings. PLoS Genet. 2, e41 (2006)

    Article  Google Scholar 

  10. Weedon, M. N. et al. A common variant of HMGA2 is associated with adult and childhood height in the general population. Nature Genet. 39, 1245–1250 (2007)

    Article  CAS  Google Scholar 

  11. Weedon, M. N. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genet. 40, 575–583 (2008)

    Article  CAS  Google Scholar 

  12. Sanna, S. et al. Common variants in the GDF5-UQCC region are associated with variation in human height. Nature Genet. 40, 198–203 (2008)

    Article  CAS  Google Scholar 

  13. Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nature Genet. 40, 584–591 (2008)

    Article  CAS  Google Scholar 

  14. Soranzo, N., Rivadeneira, F., Chinappen-Horsley, U. & Malkina, I. Meta-analysis of genome-wide scans for human adult stature in humans identifies novel loci and associations with measures of skeletal frame size. PLoS Genet. 5, e1000445 (2009)

    Article  Google Scholar 

  15. Gudbjartsson, D. F. et al. Many sequence variants affecting diversity of adult human height. Nature Genet. 40, 609–615 (2008)

    Article  CAS  Google Scholar 

  16. Johansson, A. et al. Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. Hum. Mol. Genet. 18, 373–380 (2009)

    Article  CAS  Google Scholar 

  17. Estrada, K. et al. A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation. Hum. Mol. Genet. 18, 3516–3524 (2009)

    Article  CAS  Google Scholar 

  18. Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–752 (2009)

    Article  ADS  CAS  Google Scholar 

  19. Park, J. H. et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nature Genet. 42, 570–575 (2010)

    Article  CAS  Google Scholar 

  20. Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009)

    Article  Google Scholar 

  21. Segrè, A. V. et al. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 6, e1001058 (2010)

    Article  Google Scholar 

  22. Neptune, E. R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nature Genet. 33, 407–411 (2003)

    Article  CAS  Google Scholar 

  23. Superti-Furga, A. & Unger, S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am. J. Med. Genet. A 143, 1–18 (2007)

    Article  Google Scholar 

  24. Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003)

    Article  CAS  Google Scholar 

  25. Weinstein, M., Xu, X., Ohyama, K. & Deng, C. X. FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. Development 125, 3615–3623 (1998)

    CAS  PubMed  Google Scholar 

  26. Goldstein, D. B. Common genetic variation and human traits. N. Engl. J. Med. 360, 1696–1698 (2009)

    Article  CAS  Google Scholar 

  27. Dickson, S. P., Wang, K., Krantz, I., Hakonarson, H. & Goldstein, D. B. Rare variants create synthetic genome-wide associations. PLoS Biol. 8, e1000294 (2010)

    Article  Google Scholar 

  28. Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nature Genet. 42, 565–569 (2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Several participating studies are members of the CHARGE and ENGAGE consortia. We acknowledge funding from the following organizations: the Academy of Finland (104781, 117797, 120315, 121584, 126925, 129269, 129494, 129680, 213506); Affymetrix for genotyping services (N02-HL-6-4278); Agency for Science, Technology and Research of Singapore; ALF/LUA Gothenburg; Althingi (the Icelandic Parliament); Amgen; AstraZeneca AB; Australian National Health and Medical Research Council (241944, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 496688, 552485, 613672); Australian Research Council (DP0770096); Biocentrum Helsinki; Boston Obesity Nutrition Research Center (DK46200); British Diabetes Association; British Heart Foundation (PG/02/128); British Heart Foundation Centre for Research Excellence, Oxford; CamStrad; Cancer Research UK; Centre for Neurogenomics and Cognitive Research; Chief Scientist Office of the Scottish Government (CZB/4/279); Council of Health of the Academy of Finland; DIAB Core project of the German Network of Diabetes; Diabetes UK; Donald W. Reynolds Foundation; Emil and Vera Cornell Foundation; Erasmus MC; Estonian Government (SF0180142s08); European Commission (201413, ECOGENE:205419, BBMRI:212111, OPENGENE:245536, ENGAGE:HEALTH-F4-2007-201413, EURODIA:LSHG-CT-2004-518153, EU/WLRT-2001-01254, HEALTH-F2-2008-ENGAGE, HEALTH-F4-2007-201550, LSH-2006-037593, LSHG-CT-2006-018947, LSHG-CT-2006-01947, Procardis:LSHM-CT-2007-037273, POLYGENE:LSHC-CT-2005, QLG1-CT-2000-01643, QLG2-CT-2002-01254, DG XII, Marie Curie Intra-European Fellowship); Eve Appeal; Finnish Ministry of Education; Finnish Diabetes Research Foundation; Finnish Diabetes Research Society; Finnish Foundation for Cardiovascular Research; Finnish Medical Society; Finska Läkaresällskapet; Folkhälsan Research Foundation; Fondation LeDucq; Foundation for Life and Health in Finland; Foundation for Strategic Research; GEN-AU-Programme ‘GOLD’; Genetic Association Information Network; German Bundesministerium fuer Forschung und Technology (01 AK 803 A-H, 01 IG 07015 G); German Federal Ministry of Education and Research (01GS0831); German Ministry for Health, Welfare and Sports; German Ministry of Cultural Affairs; German Ministry of Education, Culture and Science; German National Genome Research Net (01GS0823, 01ZZ0103, 01ZZ0403, 01ZZ9603, 03ZIK012); German Research Council (KFO-152); GlaxoSmithKline; Göteborg Medical Society; Gyllenberg Foundation; Helmholtz Center Munich; Juvenile Diabetes Research Foundation International (U01 DK062418); Karolinska Institute; Knut and Alice Wallenberg Foundation; Lundberg Foundation; March of Dimes (6-FY-09-507); MC Health; Medical Research Council UK (G0000649, G0000934, G0500539, G0600331, G0601261, G9521010D, PrevMetSyn); Microarray Core Facility of the Interdisciplinary Centre for Clinical Research (B27); Mid-Atlantic Nutrition and Obesity Research Center of Maryland (P30 DK072488); Ministry of Health and Department of Educational Assistance (South Tyrol, Italy); Ministry of Science, Education and Sport of the Republic of Croatia (216-1080315-0302); Montreal Heart Institute Foundation; Närpes Health Care Foundation; National Cancer Institute; National Institute for Health Research Cambridge Biomedical Research Centre; National Institute for Health Research Oxford Biomedical Research Centre; National Institute for Health Research Comprehensive Biomedical Research Centre; National Institutes of Health (263-MA-410953, AA014041, AA07535, AA10248, AA13320, AA13321, AA13326, CA047988, CA49449, CA50385, CA65725, CA67262, CA87969, DA12854, DK062370, DK063491, DK072193, DK079466, DK080145, DK58845, HG002651, HG005214, HG005581, HL043851, HL084729, HL69757, HL71981, K08-AR055688, K23-DK080145, K99-HL094535, M01-RR00425, MH084698, N01-AG12100, N01-AG12109, N01-HC15103, N01-HC25195, N01-HC35129, N01-HC45133, N01-HC55015, N01-HC55016, N01-HC55018–N01-HC55022, N01-HC55222, N01-HC75150, N01-HC85079–N01-HC85086, N01-HG65403, R01-AG031890, R01 CA104021, R01-DK068336, R01-DK073490, R01-DK075681, R01-DK075787, R01-HL086694, R01-HL087641, R01-HL087647, R01-HL087652, R01-HL087676, R01-HL087679, R01-HL087700, R01-HL088119, R01-HL59367, R01-MH059160, R01-MH59565, R01-MH59566, R01-MH59571, R01-MH59586, R01-MH59587, R01-MH59588, R01-MH60870, R01-MH60879, R01-MH61675, R01-MH63706, R01-MH67257, R01-MH79469, R01-MH81800, RL1-MH083268, T32-HG00040, U01-CA098233, U01-GM074518, U01-HG004399, U01-HG004402, U01-HL080295, U01-HL084756, U01-HL72515, U01-MH79469, U01-MH79470, U54-RR020278, UL1-RR025005, Z01-AG00675, Z01-AG007380, Z01-HG000024; contract HHSN268200625226C; ADA Mentor-Based Postdoctoral Fellowship; Pew Scholarship for the Biomedical Sciences); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Organisation for Scientific Research (investment number 175.010.2005.011, 911-03-012); Netherlands Organization for the Health Research and Development (10-000-1002); Netherlands Scientific Organization (904-61-090, 904-61-193, 480-04-004, 400-05-717, Center for Medical Systems Biology (NOW Genomics), SPI 56-464-1419) ; NIA Intramural Research Program; Nordic Center of Excellence in Disease Genetics; Novo Nordisk Foundation; Ollqvist Foundation; Paavo Nurmi Foundation; Perklén Foundation; Petrus and Augusta Hedlunds Foundation; Queensland Institute of Medical Research; Radboud University Nijmegen Medical Centre; Research Institute for Diseases in the Elderly (014-93-015); Royal Swedish Academy of Science; Sahlgrenska Center for Cardiovascular and Metabolic Research (A305:188); Siemens Healthcare, Erlangen, Germany; Signe and Ane Gyllenberg Foundation; Sigrid Juselius Foundation; Social Insurance Institution of Finland; Social Ministry of the Federal State of Mecklenburg-West Pomerania; South Tyrolean Sparkasse Foundation; Stockholm County Council (560183); Support for Science Funding programme; Susan G. Komen Breast Cancer Foundation; Swedish Cancer Society; Swedish Cultural Foundation in Finland; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation; Swedish Medical Research Council (K2007-66X-20270-01-3, 8691); Swedish National Cancer Institute; Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation (33CSCO-122661); Torsten and Ragnar Söderberg’s Foundation; Vandervell Foundation; Västra Götaland Foundation; Wellcome Trust (072960, 075491, 079557, 079895, 083270, 068545/Z/02, 076113/B/04/Z, 076113/C/04/Z, 076113/C/04/Z, 077016/Z/05/Z, 081682/Z/06/Z, 084183/Z/07/Z, 085301/Z/08/Z, 086596/Z/08/Z, 091746/Z/10/Z; Wellcome Trust Research Career Development Fellowship); Western Australian Genetic Epidemiology Resource and the Western Australian DNA Bank (both National Health and Medical Research Council of Australia Enabling Facilities). A detailed list of acknowledgements by study is given in the Supplementary Information.

Author information

Authors and Affiliations

Authors

Contributions

This work was done under the auspices of the Genetic Investigation of ANthropocentric Traits (GIANT) Consortium. Author contributions and roles are listed in the Supplementary Information.

Corresponding authors

Correspondence to Michael N. Weedon, Gonçalo R. Abecasis, Kari Stefansson, Timothy M. Frayling or Joel N. Hirschhorn.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, additional references, Supplementary Tables 1-13, Supplementary Figures 1-3 with legends, Supplementary Methods Tables 1-3 and Supplementary Notes comprising author contributions and acknowledgments. (PDF 6588 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lango Allen, H., Estrada, K., Lettre, G. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010). https://doi.org/10.1038/nature09410

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09410

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research