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

Journal name:
Nature
Volume:
467,
Pages:
832–838
Date published:
DOI:
doi:10.1038/nature09410
Received
Accepted
Published online

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.

At a glance

Figures

  1. Phenotypic variance explained by common variants.
    Figure 1: Phenotypic variance explained by common variants.

    a, Variance explained is higher when SNPs not reaching genome-wide significance are included in the prediction model. The y axis represents the proportion of variance explained at different P-value thresholds from stage 1. Results are given for five studies that were not part of stage 1. The proportion of variation explained by the 180 SNPs is shown in the column to the right of the graph. b, Cumulative number of susceptibility loci expected to be discovered, including already identified loci and as yet undetected loci. The projections are based on loci that achieved a significance level of P<5×10−8 in the initial scan and the distribution of their effect sizes in stage 2. The dotted red line corresponds to expected phenotypic variance explained by the 110 loci that reached genome-wide significance in stage 1, were replicated in stage 2 and had at least 1% power.

  2. Example of a locus with a secondary signal before (a) and after (b) conditioning.
    Figure 2: Example of a locus with a secondary signal before (a) and after (b) conditioning.

    The plot is centred on the conditioned SNP (purple diamond) at the locus. The values of r2 are based on the CEU HapMap II samples. The blue line and right-hand y axis represent CEU HapMap II recombination rates. The figure was created using LocusZoom (http://csg.sph.umich.edu/locuszoom/).

  3. Loci associated with height contain genes related to each other.
    Figure 3: Loci associated with height contain genes related to each other.

    a, One hundred and eighty height-associated SNPs. The y-axis plots GRAIL P values on a log scale. The histogram corresponds to the distribution of GRAIL P values for 1,000 sets of 180 matched SNPs. The scatter plot represents GRAIL results for the 180 height SNPs (blue dots). The black horizontal line marks the median of the GRAIL P values (P = 0.14). The top ten keywords linking the genes were: ‘growth’, ‘kinase’, ‘factor’, ‘transcription’, ‘signalling’, ‘binding’, ‘differentiation’, ‘development’, ‘insulin’, ‘bone’. b, Representation of the connections between SNPs and corresponding genes for the 42 SNPs with GRAIL P<0.01. Thicker and redder lines imply stronger literature-based connectivity.

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, 93629367 (2009)
  2. Galton, F. Regression towards mediocrity in hereditary stature. J. R. Anthropol. Inst. 5, 329348 (1885)
  3. Fisher, R. A. The correlation between relatives on the supposition of Mendelian inheritance. Trans. R. Soc. Edinb. 52, 399433 (1918)
  4. Frazer, K. A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851861 (2007)
  5. Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 9971004 (1999)
  6. Reich, D. E. & Goldstein, D. B. Detecting association in a case-control study while correcting for population stratification. 20, 416 (2001)
  7. Campbell, C. D. et al. Demonstrating stratification in a European American population. Nature Genet. 37, 868872 (2005)
  8. Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature 461, 747753 (2009)
  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)
  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, 12451250 (2007)
  11. Weedon, M. N. et al. Genome-wide association analysis identifies 20 loci that influence adult height. Nature Genet. 40, 575583 (2008)
  12. Sanna, S. et al. Common variants in the GDF5-UQCC region are associated with variation in human height. Nature Genet. 40, 198203 (2008)
  13. Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nature Genet. 40, 584591 (2008)
  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)
  15. Gudbjartsson, D. F. et al. Many sequence variants affecting diversity of adult human height. Nature Genet. 40, 609615 (2008)
  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, 373380 (2009)
  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, 35163524 (2009)
  18. Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748752 (2009)
  19. Park, J. H. et al. Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nature Genet. 42, 570575 (2010)
  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)
  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)
  22. Neptune, E. R. et al. Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome. Nature Genet. 33, 407411 (2003)
  23. Superti-Furga, A. & Unger, S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am. J. Med. Genet. A 143, 118 (2007)
  24. Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 11391147 (2003)
  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, 36153623 (1998)
  26. Goldstein, D. B. Common genetic variation and human traits. N. Engl. J. Med. 360, 16961698 (2009)
  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)
  28. Yang, J. et al. Common SNPs explain a large proportion of the heritability for human height. Nature Genet. 42, 565569 (2010)

Download references

Author information

  1. These authors contributed equally to this work.

    • Hana Lango Allen,
    • Karol Estrada,
    • Guillaume Lettre,
    • Sonja I. Berndt,
    • Michael N. Weedon,
    • Fernando Rivadeneira,
    • Gonçalo R. Abecasis,
    • Kari Stefansson,
    • Timothy M. Frayling &
    • Joel N. Hirschhorn

Affiliations

  1. Genetics of Complex Traits, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX1 2LU, UK.

    • Hana Lango Allen,
    • Michael N. Weedon,
    • Andrew R. Wood,
    • John R. B. Perry,
    • Andrew T. Hattersley &
    • Timothy M. Frayling
  2. Department of Epidemiology, Erasmus Medical Centre, 3015 GE Rotterdam, The Netherlands.

    • Karol Estrada,
    • Fernando Rivadeneira,
    • Yurii S. Aulchenko,
    • Najaf Amin,
    • Joyce B. J. van Meurs,
    • Albert Hofman,
    • Cornelia M. van Duijn &
    • André G. Uitterlinden
  3. Department of Internal Medicine, Erasmus Medical Centre, 3015 GE Rotterdam, The Netherlands.

    • Karol Estrada,
    • Fernando Rivadeneira,
    • M. Carola Zillikens,
    • Marjolein J. Peters,
    • Joyce B. J. van Meurs &
    • André G. Uitterlinden
  4. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), 2300 RC Leiden, The Netherlands.

    • Karol Estrada,
    • Fernando Rivadeneira,
    • Yurii S. Aulchenko,
    • Marjolein J. Peters,
    • Joyce B. J. van Meurs,
    • Albert Hofman,
    • Cornelia M. van Duijn &
    • André G. Uitterlinden
  5. Montreal Heart Institute, Montréal, Québec H1T 1C8, Canada.

    • Guillaume Lettre,
    • Ken Sin Lo,
    • Gabrielle Boucher &
    • John D. Rioux
  6. Department of Medicine, Université de Montréal, Montréal, Québec H3T 1J4, Canada.

    • Guillaume Lettre &
    • John D. Rioux
  7. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.

    • Sonja I. Berndt,
    • Ju-Hyun Park,
    • Jianxin Shi,
    • Stephen J. Chanock &
    • Nilanjan Chatterjee
  8. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Cristen J. Willer,
    • Anne U. Jackson,
    • Robert J. Weyant,
    • Heather M. Stringham,
    • Michael Boehnke &
    • Gonçalo R. Abecasis
  9. Divisions of Genetics and Endocrinology and Program in Genomics, Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Sailaja Vedantam,
    • Cameron Palmer,
    • Elizabeth L. Altmaier,
    • Rany M. Salem,
    • Michael C. Turchin &
    • Joel N. Hirschhorn
  10. Metabolism Initiative and Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Sailaja Vedantam,
    • Elizabeth K. Speliotes,
    • Cameron Palmer,
    • Elizabeth L. Altmaier,
    • Rany M. Salem,
    • Michael C. Turchin &
    • Joel N. Hirschhorn
  11. Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.

    • Soumya Raychaudhuri,
    • Ayellet V. Segrè,
    • Benjamin F. Voight,
    • Kristin G. Ardlie &
    • Sekar Kathiresan
  12. Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 USA.

    • Soumya Raychaudhuri
  13. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • Teresa Ferreira,
    • Joshua C. Randall,
    • Reedik Mägi,
    • Inga Prokopenko,
    • Nigel W. Rayner,
    • Neil R. Robertson,
    • Andrew P. Morris,
    • John F. Peden,
    • Martin Farrall,
    • Hugh Watkins,
    • Mark I. McCarthy &
    • Cecilia M. Lindgren
  14. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Ayellet V. Segrè,
    • Benjamin F. Voight,
    • Shaun Purcell &
    • Sekar Kathiresan
  15. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Ayellet V. Segrè &
    • Benjamin F. Voight
  16. Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Elizabeth K. Speliotes &
    • Lee M. Kaplan
  17. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

    • Eleanor Wheeler,
    • Nicole Soranzo,
    • Elin Grundberg,
    • Panos Deloukas,
    • Inês Barroso,
    • Willem H. Ouwehand &
    • Leena Peltonen
  18. Department of Twin Research and Genetic Epidemiology, King’s College London, Lambeth Palace Road, London SE1 7EH, UK.

    • Nicole Soranzo,
    • Massimo Mangino &
    • Timothy D. Spector
  19. Queensland Statistical Genetics Laboratory, Queensland Institute of Medical Research, Queensland 4006, Australia.

    • Jian Yang &
    • Peter M. Visscher
  20. deCODE Genetics, 101 Reykjavik, Iceland.

    • Daniel Gudbjartsson,
    • Gudmar Thorleifsson,
    • Valgerdur Steinthorsdottir,
    • G. Bragi Walters,
    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  21. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

    • Nancy L. Heard-Costa &
    • Larry D. Atwood
  22. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Lu Qi,
    • Tsegaselassie Workalemahu,
    • Frank B. Hu &
    • David J. Hunter
  23. Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Lu Qi,
    • Frank B. Hu &
    • David J. Hunter
  24. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert Vernon Smith,
    • Thor Aspelund,
    • Gudny Eiriksdottir &
    • Vilmundur Gudnason
  25. University of Iceland, 101 Reykjavik, Iceland.

    • Albert Vernon Smith,
    • Thor Aspelund &
    • Vilmundur Gudnason
  26. McGill University and Genome Québec Innovation Centre, Montréal, Québec H3A 1A4, Canada.

    • Tomi Pastinen,
    • Elin Grundberg,
    • Tony Kwan &
    • Dominique J. Verlaan
  27. Department of Human Genetics, McGill University Health Centre, McGill University, Montréal, Québec H3G 1A4, Canada.

    • Tomi Pastinen,
    • Elin Grundberg,
    • Tony Kwan &
    • Dominique J. Verlaan
  28. Department of Medical Genetics, McGill University Health Centre, McGill University, Montréal, Québec H3G 1A4, Canada.

    • Tomi Pastinen
  29. Departments of Epidemiology and Biostatistics, Harvard School of Public Health, Cambridge, Massachusetts 02138, USA.

    • Liming Liang
  30. Regensburg University Medical Center, Department of Epidemiology and Preventive Medicine, 93053 Regensburg, Germany.

    • Iris M. Heid &
    • Thomas W. Winkler
  31. Institute of Epidemiology, Helmholtz Zentrum München – German Research Center for Environmental Health, 85764 Neuherberg, Germany.

    • Iris M. Heid,
    • Eva Albrecht,
    • Martina Müller,
    • Thomas Illig,
    • Christian Gieger &
    • H.-Erich Wichmann
  32. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK.

    • Jian’an Luan,
    • Jing Hua Zhao,
    • Tuomas O. Kilpeläinen,
    • Nicholas J. Wareham &
    • Ruth J. F. Loos
  33. Faculty of Land and Environment, University of Melbourne, Parkville 3010, Australia.

    • Michael E. Goddard
  34. Department of Primary Industries, Bundoora, Victoria 3086,, Australia.

    • Michael E. Goddard
  35. Department of Genetics and Pathology, Rudbeck Laboratory, University of Uppsala, SE-75185 Uppsala, Sweden.

    • Åsa Johansson,
    • Wilmar Igl &
    • Ulf Gyllensten
  36. Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), N-7489 Trondheim, Norway.

    • Åsa Johansson
  37. Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.

    • Mary F. Feitosa,
    • Shamika Ketkar,
    • Michael A. Province &
    • Ingrid B. Borecki
  38. Estonian Genome Center, University of Tartu, Tartu 50410, Estonia.

    • Tõnu Esko,
    • Mari-Liis Tammesoo,
    • Helene Alavere,
    • Mari Nelis &
    • Andres Metspalu
  39. Estonian Biocenter, Tartu 51010, Estonia.

    • Tõnu Esko,
    • Mari Nelis &
    • Andres Metspalu
  40. Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.

    • Tõnu Esko,
    • Mari Nelis &
    • Andres Metspalu
  41. Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland.

    • Toby Johnson,
    • Zoltán Kutalik,
    • Jacques S. Beckmann,
    • Sven Bergmann &
    • Carlo Rivolta
  42. Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.

    • Toby Johnson,
    • Zoltán Kutalik &
    • Sven Bergmann
  43. Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK.

    • Toby Johnson
  44. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK.

    • Toby Johnson,
    • Mark J. Caulfield &
    • Patricia B. Munroe
  45. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Peter Kraft,
    • Frank B. Hu &
    • David J. Hunter
  46. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Peter Kraft
  47. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.

    • Inga Prokopenko,
    • Nigel W. Rayner,
    • Neil R. Robertson,
    • Mark I. McCarthy &
    • Cecilia M. Lindgren
  48. Hudson Alpha Institute for Biotechnology, Huntsville, Alabama 35806, USA.

    • Devin Absher
  49. Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt-University Greifswald, 17487 Greifswald, Germany.

    • Florian Ernst
  50. Cardiovascular Health Research Unit and Department of Medicine, University of Washington, Seattle, Washington 98101, USA.

    • Nicole L. Glazer
  51. MRC Human Genetics Unit, Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, Scotland, UK.

    • Caroline Hayward,
    • Veronique Vitart,
    • Alan F. Wright &
    • Igor Rudan
  52. Department of Biological Psychology, VU University Amsterdam, 1081 BT Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga,
    • Eco J. C. Geus,
    • Gonneke Willemsen &
    • Dorret I. Boomsma
  53. Core Genotyping Facility, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 21702, USA.

    • Kevin B. Jacobs
  54. Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.

    • Joshua W. Knowles,
    • Themistocles L. Assimes &
    • Thomas Quertermous
  55. Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, USA.

    • Keri L. Monda &
    • Kari E. North
  56. Andrija Stampar School of Public Health, Medical School, University of Zagreb, 10000 Zagreb, Croatia.

    • Ozren Polasek,
    • Ivana Kolcic &
    • Lina Zgaga
  57. Gen-Info Ltd, 10000 Zagreb, Croatia.

    • Ozren Polasek
  58. Universität zu Lübeck, Institut für Medizinische Biometrie und Statistik, 23562 Lübeck, Germany.

    • Michael Preuss &
    • Inke R. König
  59. Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.

    • Jonathan P. Tyrer
  60. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.

    • Fredrik Wiklund,
    • Henrik Grönberg,
    • Per Hall &
    • Erik Ingelsson
  61. Center for Human Genomics, Wake Forest University, Winston-Salem, North Carolina 27157, USA.

    • Jianfeng Xu
  62. Neurogenetics Laboratory, Queensland Institute of Medical Research, Queensland 4006, Australia.

    • Dale R. Nyholt
  63. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014, Helsinki, Finland.

    • Niina Pellikka,
    • Markus Perola,
    • Ida Surakka,
    • Johannes Kettunen,
    • Elisabeth Widen,
    • Samuli Ripatti,
    • Jaakko Kaprio &
    • Leena Peltonen
  64. National Institute for Health and Welfare, Department of Chronic Disease Prevention, Unit of Public Health Genomics, FIN-00014 Helsinki, Finland.

    • Niina Pellikka,
    • Markus Perola,
    • Ida Surakka,
    • Johannes Kettunen,
    • Samuli Ripatti &
    • Leena Peltonen
  65. Department of Genome Sciences, University of Washington, Seattle, 98195 Washington, USA.

    • Tushar Bhangale
  66. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA.

    • Daniel I. Chasman &
    • Paul M. Ridker
  67. Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Daniel I. Chasman,
    • Lee M. Kaplan &
    • Paul M. Ridker
  68. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Constance Chen
  69. Department of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine, Imperial College London, London W2 1PG, UK.

    • Lachlan Coin,
    • Ulla Sovio,
    • Paul Elliott &
    • Marjo-Riitta Jarvelin
  70. Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Crawley, Western Australia 6009, Australia.

    • Matthew N. Cooper,
    • Robert W. Lawrence,
    • Jennie Hui &
    • Lyle J. Palmer
  71. Royal National Hospital for Rheumatic Diseases and University of Bath, Bath BA1 1RL, UK.

    • Anna L. Dixon
  72. Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    • Quince Gibson,
    • Shen Haiqing,
    • Alan R. Shuldiner &
    • Jeffrey R. O’Connell
  73. Genetics Department, Rosetta Inpharmatics, a Wholly Owned Subsidiary of Merck & Co Inc., Seattle, Washington 98109, USA.

    • Ke Hao
  74. Department of Internal Medicine, University of Oulu, 90014 Oulu, Finland.

    • M. Juhani Junttila &
    • Heikki V. Huikuri
  75. MGH Weight Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Lee M. Kaplan
  76. Stanford University School of Medicine, Stanford, California 93405, USA.

    • Douglas F. Levinson
  77. Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 413 45 Gothenburg, Sweden.

    • Mattias Lorentzon,
    • Liesbeth Vandenput &
    • Claes Ohlsson
  78. Departments of Biostatistics, University of Washington, Seattle, Washington 98195, USA.

    • Barbara McKnight &
    • Alice M. Arnold
  79. Ludwig-Maximilians- Universität, Department of Medicine I, University Hospital Grosshadern, 81377 Munich, Germany.

    • Martina Müller
  80. Ludwig-Maximilians-Universität, Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, 81377 Munich, Germany.

    • Martina Müller &
    • H.-Erich Wichmann
  81. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.

    • Julius Suh Ngwa,
    • Charles C. White &
    • L. Adrienne Cupples
  82. The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Shaun Purcell &
    • Leena Peltonen
  83. Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Shaun Purcell
  84. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.

    • Suzanne Rafelt &
    • Nilesh J. Samani
  85. University of Milan, Department of Medicine, Surgery and Dentistry, 20139 Milan, Italy.

    • Erika Salvi &
    • Daniele Cusi
  86. KOS Genetic Srl, 20123 Milan, Italy.

    • Erika Salvi
  87. Istituto di Neurogenetica e Neurofarmacologia del CNR, Monserrato, 09042 Cagliari, Italy.

    • Serena Sanna,
    • Andrea Maschio,
    • Antonella Mulas &
    • Manuela Uda
  88. Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK.

    • John R. Thompson &
    • Nilesh J. Samani
  89. Department of Health Sciences, University of Leicester, University Road, Leicester LE1 7RH, UK.

    • John R. Thompson
  90. Universität zu Lübeck, Institut für Medizinische Biometrie und Statistik, 23562 Lübeck, Germany.

    • Andreas Ziegler
  91. Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden.

    • Peter Almgren &
    • Leif C. Groop
  92. Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK.

    • Anthony J. Balmforth &
    • Alistair S. Hall
  93. Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, Scotland, UK.

    • Harry Campbell,
    • Sarah H. Wild &
    • James F. Wilson
  94. University Vita-Salute San Raffaele, Division of Nephrology and Dialysis, 20132 Milan, Italy.

    • Lorena Citterio &
    • Laura Zagato
  95. Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano/Bozen, 39100, Italy. Affiliated Institute of the University of Lübeck, Lübeck, Germany.

    • Alessandro De Grandi,
    • Andrew A. Hicks,
    • Irene Pichler &
    • Peter P. Pramstaller
  96. British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TA, UK.

    • Anna Dominiczak
  97. Northshore University Healthsystem, Evanston, Illinois 60201, USA.

    • Jubao Duan,
    • Alan R. Sanders &
    • Pablo V. Gejman
  98. Cardiovascular Epidemiology and Genetics, Institut Municipal D’investigacio Medica and CIBER Epidemiología y Salud Pública, Barcelona, Spain.

    • Roberto Elosua
  99. Department of General Practice and Primary Health Care, University of Helsinki, 00014, Helsinki, Finland.

    • Johan G. Eriksson
  100. National Institute for Health and Welfare, 00271 Helsinki, Finland.

    • Johan G. Eriksson &
    • Eero Kajantie
  101. Helsinki University Central Hospital, Unit of General Practice, 00280 Helsinki, Finland.

    • Johan G. Eriksson
  102. Folkhalsan Research Centre, 00250 Helsinki, Finland.

    • Johan G. Eriksson
  103. Vasa Central Hospital, 65130 Vasa, Finland.

    • Johan G. Eriksson
  104. Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA.

    • Nelson B. Freimer
  105. Hypertension and Cardiovascular Prevention Center, University of Sassari, 07100 Sassari, Italy.

    • Nicola Glorioso
  106. Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, 90014 Oulu, Finland.

    • Anna-Liisa Hartikainen &
    • Anneli Pouta
  107. National Institute for Health and Welfare, Department of Chronic Disease Prevention, Chronic Disease Epidemiology and Prevention Unit, 00014, Helsinki, Finland.

    • Aki S. Havulinna,
    • Seppo Koskinen &
    • Veikko Salomaa
  108. PathWest Laboratory of Western Australia, Department of Molecular Genetics, J Block, QEII Medical Centre, Nedlands, Western Australia 6009, Australia.

    • Jennie Hui &
    • John P. Beilby
  109. Busselton Population Medical Research Foundation Inc., Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.

    • Jennie Hui,
    • John P. Beilby,
    • Arthur W. Musk &
    • Lyle J. Palmer
  110. National Institute for Health and Welfare, Department of Chronic Disease Prevention, Population Studies Unit, 20720 Turku, Finland.

    • Antti Jula
  111. Institute of Health Sciences, University of Oulu, 90014 Oulu, Finland.

    • Markku Koiranen &
    • Marjo-Riitta Jarvelin
  112. Interdisciplinary Centre for Clinical Research, University of Leipzig, 04103 Leipzig, Germany.

    • Peter Kovacs
  113. Finnish Institute of Occupational Health, 90220 Oulu, Finland.

    • Jaana Laitinen
  114. Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.

    • Jianjun Liu
  115. Transplantation Laboratory, Haartman Institute, University of Helsinki, 00014, Helsinki, Finland.

    • Marja-Liisa Lokki
  116. Croatian Centre for Global Health, School of Medicine, University of Split, Split 21000, Croatia.

    • Ana Marusic &
    • Igor Rudan
  117. Institute of Human Genetics, Klinikum rechts der Isar der Technischen Universität München, 81675 Munich, Germany.

    • Thomas Meitinger
  118. Institute of Human Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany.

    • Thomas Meitinger
  119. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

    • Guillaume Paré
  120. Amgen, Cambridge, Massachusetts 02139, USA.

    • Alex N. Parker
  121. Department of Cardiovascular Medicine, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.

    • John F. Peden,
    • Martin Farrall &
    • Hugh Watkins
  122. Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Greifswald, 17475 Greifswald, Germany.

    • Astrid Petersmann
  123. Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, 00014, Helsinki, Finland.

    • Kirsi H. Pietiläinen &
    • Jaakko Kaprio
  124. Obesity Research unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.

    • Kirsi H. Pietiläinen &
    • Aila Rissanen
  125. National Institute for Health and Welfare, 90101 Oulu, Finland.

    • Anneli Pouta &
    • Marjo-Riitta Jarvelin
  126. Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden.

    • Martin Ridderstråle &
    • Olle Melander
  127. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

    • Jerome I. Rotter &
    • Talin Haritunians
  128. Department of Haematology, University of Cambridge, Cambridge CB2 0PT, UK.

    • Jennifer G. Sambrook &
    • Willem H. Ouwehand
  129. NHS Blood and Transplant, Cambridge Centre, Cambridge CB2 0PT, UK.

    • Jennifer G. Sambrook &
    • Willem H. Ouwehand
  130. Institut für Community Medicine, 17489 Greifswald, Germany.

    • Carsten Oliver Schmidt,
    • Wolfgang Hoffman &
    • Henry Völzke
  131. Division of Cardiology, Cardiovascular Laboratory, Helsinki University Central Hospital, 00029 Helsinki, Finland.

    • Juha Sinisalo &
    • Markku S. Nieminen
  132. Department of Psychiatry/EMGO Institute, VU University Medical Center, 1081 BT Amsterdam, The Netherlands.

    • Jan H. Smit &
    • Brenda W. Penninx
  133. Department of Physiatrics, Lapland Central Hospital, 96101 Rovaniemi, Finland.

    • Paavo Zitting
  134. Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.

    • Martin Farrall
  135. Avon Longitudinal Study of Parents and Children (ALSPAC) Laboratory, Department of Social Medicine, University of Bristol, Bristol BS8 2BN, UK.

    • Wendy L. McArdle
  136. Comprehensive Cancer Center East, 6501 BG Nijmegen, The Netherlands.

    • Katja K. Aben &
    • Lambertus Kiemeney
  137. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV) University Hospital, 1011 Lausanne, Switzerland.

    • Jacques S. Beckmann
  138. School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Western Australia 6009, Australia.

    • John P. Beilby
  139. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Richard N. Bergman
  140. National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Francis S. Collins
  141. Department of Endocrinology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

    • Martin den Heijer
  142. Atherosclerosis Research Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden.

    • Anders Hamsten
  143. Division of Research, Kaiser Permanente Northern California, Oakland, California 94612, USA.

    • Carlos Iribarren
  144. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California 94107, USA.

    • Carlos Iribarren
  145. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.

    • Mika Kähönen
  146. National Institute for Health and Welfare, Department of Mental Health and Substance Abuse Services, Unit for Child and Adolescent Mental Health, 00271 Helsinki, Finland.

    • Jaakko Kaprio
  147. Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Sekar Kathiresan
  148. Framingham Heart Study of the National Heart, Lung, and Blood Institute and Boston University, Framingham, Massachusetts 01702, USA.

    • Sekar Kathiresan &
    • Christopher J. O’Donnell
  149. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Sekar Kathiresan
  150. Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

    • Lambertus Kiemeney
  151. Department of Urology, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

    • Lambertus Kiemeney
  152. Zentrum für Zahn-, Mund- und Kieferheilkunde, 17489 Greifswald, Germany.

    • Thomas Kocher
  153. Laboratory of Epidemiology, Demography, Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.

    • Lenore J. Launer &
    • Tamara B. Harris
  154. Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, 33520 Tampere, Finland.

    • Terho Lehtimäki
  155. Department of Medicine, Division of Geriatrics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.

    • Tom H. Mosley Jr
  156. School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia 6009, Australia.

    • Arthur W. Musk
  157. National, Lung, and Blood Institute, National Institutes of Health, Framingham, Massachusetts 01702, USA.

    • Christopher J. O’Donnell
  158. Department of Clinical Genetics, Erasmus Medical Centre, 3015 GE Rotterdam, The Netherlands.

    • Ben Oostra
  159. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and the Department of Clinical Physiology, Turku University Hospital, 20520 Turku, Finland.

    • Olli Raitakari
  160. Universität zu Lübeck, Medizinische Klinik II, 23562 Lübeck, Germany.

    • Heribert Schunkert &
    • Jeanette Erdmann
  161. Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.

    • Alan R. Shuldiner
  162. Cardiovascular Health Research Unit, University of Washington, Seattle, Washington 98101, USA.

    • David S. Siscovick
  163. Departments of Medicine and Epidemiology, University of Washington, Seattle, Washington 98195, USA.

    • David S. Siscovick
  164. Department of Medicine, University of Leipzig, 04103 Leipzig, Germany.

    • Michael Stumvoll &
    • Anke Tönjes
  165. LIFE Study Centre, University of Leipzig, Leipzig, Germany.

    • Michael Stumvoll
  166. Coordination Centre for Clinical Trials, University of Leipzig, Härtelstrasse 16–18, 04103 Leipzig, Germany.

    • Anke Tönjes
  167. National Institute for Health and Welfare, Diabetes Prevention Unit, 00271 Helsinki, Finland.

    • Jaakko Tuomilehto
  168. Hjelt Institute, Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.

    • Jaakko Tuomilehto
  169. South Ostrobothnia Central Hospital, 60220 Seinajoki, Finland.

    • Jaakko Tuomilehto
  170. Department of Human Genetics and Center of Medical Systems Biology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands.

    • Gert-Jan van Ommen
  171. Department of Medicine, University of Turku and Turku University Hospital, 20520 Turku, Finland.

    • Jorma Viikari
  172. Department of Psychiatry and Midwest Alcoholism Research Center, Washington University School of Medicine, St Louis, Missouri 63108, USA.

    • Andrew C. Heath
  173. Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Queensland 4006, Australia.

    • Nicholas G. Martin
  174. Molecular Epidemiology Laboratory, Queensland Institute of Medical Research, Queensland 4006, Australia.

    • Grant W. Montgomery
  175. Division of Biostatistics,Washington University School of Medicine, St Louis, Missouri 63110, USA.

    • Michael A. Province &
    • Ingrid B. Borecki
  176. Department of Forensic Molecular Biology, Erasmus Medical Centre, 3015 GE Rotterdam, The Netherlands.

    • Manfred Kayser
  177. Collaborative Health Studies Coordinating Center, Seattle, Washington 98115, USA.

    • Alice M. Arnold
  178. Human Genetics Center and Institute of Molecular Medicine and Division of Epidemiology, University of Texas Health Science Center, Houston, Texas 77030, USA.

    • Eric Boerwinkle
  179. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany.

    • Christian Hengstenberg
  180. Regensburg University Medical Center, Innere Medizin II, 93053 Regensburg, Germany.

    • Christian Hengstenberg
  181. Centre National de Genotypage, Evry, Paris 91057, France.

    • G. Mark Lathrop
  182. Christian-Albrechts-University, University Hospital Schleswig-Holstein, Institute for Clinical Molecular Biology and Department of Internal Medicine I, Schittenhelmstrasse 12, 24105 Kiel, Germany.

    • Stefan Schreiber
  183. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.

    • Dawn Waterworth &
    • Vincent Mooser
  184. University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 OQQ, UK.

    • Inês Barroso
  185. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Karen L. Mohlke
  186. Division of Intramural Research, National Heart, Lung, and Blood Institute, Framingham Heart Study, Framingham, Massachusetts 01702, USA.

    • Caroline S. Fox
  187. New York University Medical Center, New York, New York 10016, USA.

    • Richard B. Hayes
  188. Biocenter Oulu, University of Oulu, 90014 Oulu, Finland.

    • Marjo-Riitta Jarvelin
  189. Department of Psychiatry, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands.

    • Brenda W. Penninx
  190. Department of Psychiatry, University Medical Centre Groningen, 9713 GZ Groningen, The Netherlands.

    • Brenda W. Penninx
  191. Department of Neurology, General Central Hospital, Bolzano, Italy.

    • Peter P. Pramstaller
  192. Department of Neurology, University of Lübeck, Lübeck, Germany.

    • Peter P. Pramstaller
  193. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    • Robert C. Kaplan
  194. Carolina Center for Genome Sciences, School of Public Health, University of North Carolina Chapel Hill, Chapel Hill, North Carolina 27514, USA.

    • Kari E. North
  195. Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland 21224, USA.

    • David Schlessinger
  196. Division of Community Health Sciences, St George’s, University of London, London SW17 0RE, UK.

    • David P. Strachan
  197. Klinikum Grosshadern, 81377 Munich, Germany.

    • H.-Erich Wichmann
  198. Pacific Biosciences, Menlo Park, California 94025, USA.

    • Eric E. Schadt
  199. Sage Bionetworks, Seattle, Washington 98109, USA.

    • Eric E. Schadt
  200. Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland.

    • Unnur Thorsteinsdottir &
    • Kari Stefansson
  201. Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland.

    • Leena Peltonen
  202. NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Mark I. McCarthy
  203. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Joel N. Hirschhorn

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.

Competing financial interests

The authors declare no competing financial interests.

Author details

Supplementary information

PDF files

  1. Supplementary Information (6.4M)

    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.

Additional data