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Cited by 1,853Genetic Associations and EpidemiologyGenetics and Physical PerformanceGenetic and phenotypic traits in livestock

Defining the role of common variation in the genomic and biological architecture of adult human height

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The Electronic Medical Records and Genomics (eMERGE) Consortium, Wood, Andrew R, The MIGen Consortium, The PAGE Consortium, The LifeLines Cohort Study, Esko, Tonu, Yang, Jian, Vedantam, Sailaja +441 more·2014·Nature Genetics
DOI 10.1038/ng.3097PMC PMC4250049
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Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

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  • In the largest meta-analysis of 253,288 individuals of recent European ancestry, body height-associated SNPs were identified in LATS2 (rs1199734), TEAD1 (rs6485978, rs2099745), VGLL2 (rs1405212), and VGLL4 (rs13078528).

    “In the largest meta-analysis study using data obtained from 253,288 individuals of recent European ancestry (152), body height-associated SNPs in LATS2 (rs1199734), TEAD1 (rs6485978, rs2099745), VGLL2 (rs1405212) and VGLL4 (rs13078528) were identified.”

    From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [152]

    The Results report a height GWAS meta-analysis of 253,288 individuals of European ancestry and 697 genome-wide significant SNPs. However, the available text does not identify the claimed LATS2, TEAD1, VGLL2, or VGLL4 SNPs by name or rsID; searches for those genes and rsIDs found no confirming passage. The paper refers to supplementary tables for its SNP list, but those references do not establish the specific pairings claimed here. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Body height depends on hundreds, if not thousands, of common DNA sequence variations with small effect size.

    “and depends on hundreds, if not thousands, of common DNA sequence variations with a small effect size (152).”

    From The Hippo signal transduction network for exercise physiologists (2016) · cites this paper as [152]

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Research works printed but not linked: 2

  1. [1]Fisher RA The correlation between relatives on the supposition of Mendelian inheritance Trans. R. Soc 1918 52 399 433
  2. [21]Nüsslein-Volhard C Wieschaus E Kluding H Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster: zygotic loci on the second chromosome Roux’s Arch. Dev. Biol 1984 193 267 282 28305337

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Authors
The Electronic Medical Records and Genomics (eMERGE) Consortium, Wood, A. R., The MIGen Consortium, The PAGE Consortium, Study, T. L. C., Esko, T., Yang, J., Vedantam, S., Pers, T. H., Gustafsson, S., Chu, A. Y., Estrada, K., Luan, J., Kutalik, Z., Amin, N., Buchkovich, M. L., Croteau-Chonka, D. C., Day, F. R., Duan, Y., Fall, T., Fehrmann, R., Ferreira, T., Jackson, A. U., Karjalainen, J., Lo, K. S., Locke, A. E., Mägi, R., Mihailov, E., Porcu, E., Randall, J. C., Scherag, A., Vinkhuyzen, A. A. E., Westra, H.-J., Winkler, T. W., Workalemahu, T., Zhao, J. H., Absher, D., Albrecht, E., Anderson, D., Baron, J., Beekman, M., Demirkan, A., Ehret, G. B., Feenstra, B., Feitosa, M. F., Fischer, K., Fraser, R. M., Goel, A., Gong, J., Justice, A. E., Kanoni, S., Kleber, M. E., Kristiansson, K., Lim, U., Lotay, V., Lui, J. C., Mangino, M., Leach, I. M., Medina-Gomez, C., Nalls, M. A., Nyholt, D. R., Palmer, C. D., Pasko, D., Pechlivanis, S., Prokopenko, I., Ried, J. S., Ripke, S., Shungin, D., Stancáková, A., Strawbridge, R. J., Sung, Y. J., Tanaka, T., Teumer, A., Trompet, S., van der Laan, S. W., van Setten, J., Van Vliet-Ostaptchouk, J. V., Wang, Z., Yengo, L., Zhang, W., Afzal, U., Ärnlöv, J., Arscott, G. M., Bandinelli, S., Barrett, A., Bellis, C., Bennett, A. J., Berne, C., Blüher, M., Bolton, J. L., Böttcher, Y., Boyd, H. A., Bruinenberg, M., Buckley, B. M., Buyske, S., Caspersen, I. H., Chines, P. S., Clarke, R., Claudi-Boehm, S., Cooper, M., Daw, E. W., De Jong, P. A., Deelen, J., Delgado, G., Denny, J. C., Dhonukshe-Rutten, R., Dimitriou, M., Doney, A. S. F., Dörr, M., Eklund, N., Eury, E., Folkersen, L., Garcia, M. E., Geller, F., Giedraitis, V., Go, A. S., Grallert, H., Grammer, T. B., Gräßler, J., Grönberg, H., de Groot, L. C. P. G. M., Groves, C. J., Haessler, J., Hall, P., Haller, T., Hallmans, G., Hannemann, A., Hartman, C. A., Hassinen, M., Hayward, C., Heard-Costa, N. L., Helmer, Q., Hemani, G., Henders, A. K., Hillege, H. L., Hlatky, M. A., Hoffmann, W., Hoffmann, P., Holmen, O., Houwing-Duistermaat, J. J., Illig, T., Isaacs, A., James, A. L., Jeff, J., Johansen, B., Johansson, Å., Jolley, J., Juliusdottir, T., Junttila, J., Kho, A. N., Kinnunen, L., Klopp, N., Kocher, T., Kratzer, W., Lichtner, P., Lind, L., Lindström, J., Lobbens, S., Lorentzon, M., Lu, Y., Lyssenko, V., Magnusson, P. K. E., Mahajan, A., Maillard, M., McArdle, W. L., McKenzie, C. A., McLachlan, S., McLaren, P. J., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, K. L., Morken, M. A., Müller, G., Müller-Nurasyid, M., Musk, A. W., Narisu, N., Nauck, M., Nolte, I. M., Nöthen, M. M., Oozageer, L., Pilz, S., Rayner, N. W., Renstrom, F., Robertson, N. R., Rose, L. M., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F. R., Schunkert, H., Scott, R. A., Sehmi, J., Seufferlein, T., Shi, J., Silventoinen, K., Smit, J. H., Smith, A. V., Smolonska, J., Stanton, A. V., Stirrups, K., Stott, D. J., Stringham, H. M., Sundström, J., Swertz, M. A., Syvänen, A.-C., Tayo, B. O., Thorleifsson, G., Tyrer, J. P., van Dijk, S., van Schoor, N. M., van der Velde, N., van Heemst, D., van Oort, F. V. A., Vermeulen, S. H., Verweij, N., Vonk, J. M., Waite, L. L., Waldenberger, M., Wennauer, R., Wilkens, L. R., Willenborg, C., Wilsgaard, T., Wojczynski, M. K., Wong, A., Wright, A. F., Zhang, Q., Arveiler, D., Bakker, S. J. L., Beilby, J., Bergman, R. N., Bergmann, S., Biffar, R., Blangero, J., Boomsma, D. I., Bornstein, S. R., Bovet, P., Brambilla, P., Brown, M. J., Campbell, H., Caulfield, M. J., Chakravarti, A., Collins, R., Collins, F. S., Crawford, D. C., Cupples, L. A., Danesh, J., de Faire, U., den Ruijter, H. M., Erbel, R., Erdmann, J., Eriksson, J. G., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N. G., Forrester, T., Gansevoort, R. T., Gejman, P. V., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, D. W., Hall, A. S., Harris, T. B., Hattersley, A. T., Heath, A. C., Hengstenberg, C., Hicks, A. A., Hindorff, L. A., Hingorani, A. D., Hofman, A., Hovingh, G. K., Humphries, S. E., Hunt, S. C., Hypponen, E., Jacobs, K. B., Jarvelin, M.-R., Jousilahti, P., Jula, A. M., Kaprio, J., Kastelein, J. J. P., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, S. M., Kiemeney, L. A., Kooner, J. S., Kooperberg, C., Koskinen, S., Kovacs, P., Kraja, A. T., Kumari, M., Kuusisto, J., Lakka, T. A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, P. A. F., Männistö, S., Manunta, P., Marette, A., Matise, T. C., McKnight, B., Meitinger, T., Moll, F. L., Montgomery, G. W., Morris, A. D., Morris, A. P., Murray, J. C., Nelis, M., Ohlsson, C., Oldehinkel, A. J., Ong, K. K., Ouwehand, W. H., Pasterkamp, G., Peters, A., Pramstaller, P. P., Price, J. F., Qi, L., Raitakari, O. T., Rankinen, T., Rao, D. C., Rice, T. K., Ritchie, M., Rudan, I., Salomaa, V., Samani, N. J., Saramies, J., Sarzynski, M. A., Schwarz, P. E. H., Sebert, S., Sever, P., Shuldiner, A. R., Sinisalo, J., Steinthorsdottir, V., Stolk, R. P., Tardif, J.-C., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M.-C., Amouyel, P., Asselbergs, F. W., Assimes, T. L., Bochud, M., Boehm, B. O., Boerwinkle, E., Bottinger, E. P., Bouchard, C., Cauchi, S., Chambers, J. C., Chanock, S. J., Cooper, R. S., de Bakker, P. I. W., Dedoussis, G., Ferrucci, L., Franks, P. W., Froguel, P., Groop, L. C., Haiman, C. A., Hamsten, A., Hayes, M. G., Hui, J., Hunter, D. J., Hveem, K., Jukema, J. W., Kaplan, R. C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N. G., März, W., Melbye, M., Moebus, S., Munroe, P. B., Njølstad, I., Oostra, B. A., Palmer, C. N. A., Pedersen, N. L., Perola, M., Pérusse, L., Peters, U., Powell, J. E., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, P. M., Rivadeneira, F., Rotter, J. I., Saaristo, T. E., Saleheen, D., Schlessinger, D., Slagboom, P. E., Snieder, H., Spector, T. D., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., van der Harst, P., Völzke, H., Walker, M., Wareham, N. J., Watkins, H., Wichmann, H.-E., Wilson, J. F., Zanen, P., Deloukas, P., Heid, I. M., Lindgren, C. M., Mohlke, K. L., Speliotes, E. K., Thorsteinsdottir, U., Barroso, I., Fox, C. S., North, K. E., Strachan, D. P., Beckmann, J. S., Berndt, S. I., Boehnke, M., Borecki, I. B., McCarthy, M. I., Metspalu, A., Stefansson, K., Uitterlinden, A. G., van Duijn, C. M., Franke, L., Willer, C. J., Price, A. L., Lettre, G., Loos, R. J. F., Weedon, M. N., Ingelsson, E., O'Connell, J. R., Abecasis, G. R., Chasman, D. I., Goddard, M. E., Visscher, P. M., Hirschhorn, J. N., & Frayling, T. M.
Affiliations
  • University of Exeter (GB)
  • Broad Institute (US)
  • Uppsala University (SE)
  • SIB Swiss Institute of Bioinformatics (CH)
  • University of North Carolina at Chapel Hill (US)
  • Washington University in St. Louis (US)
  • University Medical Center Groningen (NL)
  • Centre for Human Genetics (GB)
  • University of Michigan (US)
  • Institute of Genetic and Biomedical Research (IT)
  • The University of Queensland (AU)
  • Harvard University (US)
  • University of Cambridge (GB)
  • Helmholtz Munich (DE)
  • The Kids Research Institute Australia (AU)
  • National Institutes of Health (US)
  • Leiden University Medical Center (NL)
  • Statens Serum Institut (DK)
  • University of Tartu (EE)
  • Queen Mary University of London (GB)
  • Universität Ulm (DE)
  • Finnish Institute for Health and Welfare (FI)
  • University of Hawaii Cancer Center (US)
  • University of Eastern Finland (FI)
  • Universitätsmedizin Greifswald (DE)
  • Centre National de la Recherche Scientifique (FR)
  • National Health Service (GB)
  • Dalarna University (SE)
  • Azienda Sanitaria di Firenze (IT)
  • University of Oxford (GB)
  • Texas Biomedical Research Institute (US)
  • IFB Adiposity Diseases (DE)
  • Rutgers, The State University of New Jersey (US)
  • Heidelberg University (DE)
  • Vanderbilt University (US)
  • Harokopio University of Athens (GR)
  • University of Dundee (GB)
  • University of Helsinki (FI)
  • Kaiser Permanente (US)
  • Karolinska Institutet (SE)
  • Western General Hospital (GB)
  • Boston University (US)
  • University of Bonn (DE)
  • Norwegian University of Science and Technology (NO)
  • Erasmus MC (NL)
  • The University of Western Australia (AU)
  • NHS Blood and Transplant (GB)
  • Northwestern University (US)
  • University of Gothenburg (SE)
  • Icahn School of Medicine at Mount Sinai (US)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • University of Bristol (GB)
  • University of the West Indies (JM)
  • École Polytechnique Fédérale de Lausanne (CH)
  • King's College London (GB)
  • University Hospital Ulm (DE)
  • Brigham and Women's Hospital (US)
  • Inserm (FR)
  • Medical University of Graz (AT)
  • University of Southern California (US)
  • University of Iceland (IS)
  • University of London (GB)
  • deCODE Genetics (Iceland) (IS)
  • Institute for Integrative and Experimental Genomics (DE)
  • Cedars-Sinai Medical Center (US)
  • University Hospital Carl Gustav Carus (DE)
  • University of Milan (IT)
  • Johns Hopkins University (US)
  • University of Pisa (IT)
  • Hôpital Rangueil (FR)
  • Endeavor Health (US)
  • University Hospital of Geneva (CH)
  • University of Leeds (GB)
  • Eurac Research (IT)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University of Utah (US)
  • University of South Australia (AU)
  • Queen's University Belfast (GB)
  • Oulu University Hospital (FI)
  • Vita-Salute San Raffaele University (IT)
  • University of Washington (US)
  • University Medical Center Utrecht (NL)
  • QIMR Berghofer Medical Research Institute (AU)
  • University of Iowa (US)
  • Pennington Biomedical Research Center (US)
  • Pennsylvania State University (US)
  • University of Leicester (GB)
  • Imperial College London (GB)
  • University of Maryland, Baltimore (US)
  • Montreal Heart Institute (CA)
  • Nanyang Technological University (SG)
  • The University of Texas Health Science Center at Houston (US)
  • Albert Einstein College of Medicine (US)
  • Stanford Medicine (US)
  • University of California, Los Angeles (US)
  • Universität für Weiterbildung Krems (AT)
Corresponding author
  • Visscher, Peter M
  • Hirschhorn, Joel N
  • Frayling, Timothy M
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2014-10-05
Volume
46
Issue
11
Pages
1173-1186
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3097
PMC
PMC4250049
OpenAlex
W2139852278
Cited by
1,853
References
30
Citations by year
2026: 32 · 2025: 65 · 2024: 72 · 2023: 94 · 2022: 131 · 2021: 175 · 2020: 239 · 2019: 223 · 2018: 222 · 2017: 237 · 2016: 208 · 2015: 139 · 2014: 11 · 2013: 1 · 2012: 1
FWCI
26.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • UniSA Research Outputs Repository (University of South Australia) (acceptedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
  • Wellcome Trust (098381, 098395, 085301, 090532)
  • National Institute for Health and Care Research (NF-SI-0512-10165, NF-SI-0512-10052, NF-SI-0510-10214, NF-SI-0611-10170, RP-PG-0310-1002, NF-SI-0611-10219, NF-SI-0513-10151, NF-SI-0512-10135, NF-SI-0513-10059)
  • British Heart Foundation (FS/12/33/29561, SP/08/002/24118, RG/08/008/25291, FS/12/8/29377, RG/10/12/28456, FS/14/12/30540, PG/07/085/23349, FS/11/35/28871, RG/08/014/24067, RG/09/012/28096)
  • Novo Nordisk Fonden (NNF14OC0010513, NNF12OC1016467, NNF13OC0005785)
  • National Institutes of Health (UL1TR000124)
  • Medical Research Council (MR/K013351/1, MR/K006584/1, MR/L01629X/1, MC_UU_12015/5, MR/L003120/1, MC_UU_12015/2, MC_UU_12015/1)
  • National Heart, Lung, and Blood Institute (R01-HL-088215, R01-HL087700, R01HL117078, R01HL117626, T32HL007055, R01HL109946)
  • National Human Genome Research Institute (U01HG007419)
  • National Cancer Institute (U01CA164930, P30CA071789, P30CA015704)
  • National Institute of General Medical Sciences (P01GM099568, R25GM062459, T32GM080178, P30GM103341, R01GM075091)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK072193, U01DK062370, P30DK072488, R01DK075787, R01DK093757, P30DK063491)
  • National Center for Advancing Translational Sciences
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords
adult height, common genetic variants, genetic architecture, heritability, single nucleotide polymorphisms, growth-related genes, FGF signaling, Wnt/β-catenin signaling, chondroitin sulfate, mTOR, osteoglycin, hyaluronic acid, skeletal development, genetic loci

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