Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height

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  • Additional Information
    • Affiliation:
      1 Department of Medicine and Biochemistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada
      2 Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
      3 Beijing Genomics Institute at Shenzhen, Shenzhen, China
      4 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
      5 Montréal Heart Institute, Université de Montréal, Montréal, Québec, H1T 1C8, Canada
      6 Department of Human Genetics, McGill University, Montréal, Québec, H3A 1B1, Canada
      7 Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK
      8 The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
      9 Clinical Pharmacology and Barts and the London Genome,Centre, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK
      10 Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, 98195, USA
      11 Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, 21201, USA
      12 Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany
      13 Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
      14 Department of Quantitative Health Sciences, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
      15 Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK
      16 Center for Pharmacogenomics, College of Pharmacy, University of Florida, FL 32610 USA
      17 Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705 USA
      18 Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
      19 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
      20 MRC SGDP Centre, Institute of Psychiatry, London SE5 8AF, UK
      21 Complex Genetics Section, Department of Medical Genetics (DBG) University Medical Center Utrecht, Utrecht STR 6, The Netherlands
      22 Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
      23 Leeds Institute of Genetics Health & Therapeutics, University of Leeds, Leeds LS2 9JT, UK
      24 Department of Medical and Molecular Genetics, Indiana University, School of Medicine, 410 West 10th Street, HS4000, Indianapolis, IN 46202, USA
      25 Department of Environmental Health, Environmental and Occupational Medicine and Epidemiology Program, Harvard School of Public Health, Boston, MA 02115 USA
      26 Department of Cardiology and Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam
      27 Centre for Cardiovascular Genetics, Department of Medicine, University College London, 5 University Street, London WC1E 6JF, UK
      28 National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands
      29 Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
      30 Department of Genetics, Rosetta Inpharmatics, Seattle, WA 98109-5234, USA
      31 Scripps Genomic Medicine and Scripps Translational Science Institute, 3344 N. Torrey Pines Ct. Ste 300, La Jolla, CA 92037, USA
      32 Department of Health Sciences, University of Leicester, Adrian Building, University Rd., Leicester LE1 7RH, UK
      33 Department of Clinical Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44106, USA
      34 Department of Biostatistics, University of Washington, Seattle, WA 98195 USA
      35 Framingham Heart Study, Boston University School of Medicine, Boston, MA 02118-2526, USA
      36 University of Pennsylvania Medical Center, Pulmonary, Allergy & Critical Care Division, Philadelphia, PA 19104-6160, USA
      37 Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St., Pittsburgh, PA 15261, USA
      38 University of Dundee, Medical School, Ninewells Hospital and Medical School, DD1 9SY Dundee, UK
      39 Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 55454, USA
      40 Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC 27514, USA
      41 Harvard Medical School, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
      42 McGill University and Genome Québec Innovation Centre, Montréal, Québec H3A 1A4 Canada
      43 Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco
      44 Broad Institute of MIT and Harvard, Cambridge, MA 02115, USA
      45 Division of Cardiovascular Sciences, St George's University of London, London SW17 0RE, UK
      46 Division of Clinical Developmental Sciences, St George's University of London SW17 0RE, London, UK
      47 Cardiovascular Medicine, University of Wisconsin, Madison, WI 53792, USA
      48 Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN 37232, USA
      49 Department of Molecular Medicine, Boston University, Boston, MA 02118, USA
      50 Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
      51 Cardiovascular Medicine, Case Western Reserve University, Cleveland, OH 44106,USA
      52 Institute of Statistics, National Chiao Tung University, Hsinchu 30010, Taiwan
      53 MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
      54 BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow G12 8TA, UK
      55 Clinical Research Center (CRC), Malmö University Hospital, SE-205 02 Malmö, Sweden
      56 Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Place, Glasgow G12 8QQ, UK
      57 Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland
      58 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland
      59 Translational Genomics Research Institute, Phoenix, AZ 85004, USA
      60 TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA
      61 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, 9500 Euclid Ave./NC10, Cleveland, OH 44195, USA
      62 Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
      63 Molecular Genetics, University Medical Center Groningen, Groningen University, Groningen 9700 RB, the Netherlands
      64 Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, FL 32610, USA
      65 Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
      66 Center for Non-Communicable Diseases, Karachi, Pakistan
      67 Departments of Medicine and Human Genetics, McGill University, Montréal, Québec H3A 1B1, Canada
      68 Human Genetics Center and Div. of Epidemiology, 1200 Herman Pressler, Suite E-447, Houston, TX 77030, USA
      69 Department of Genetics, University Medical Center Groningen and Groningen University, 9700 RB Groningen, The Netherlands
      70 National Heart, Lung, and Blood Institute (NHLBI), Division of Cardiovascular Sciences, Bethesda, MD 20892, USA
      71 Centre for Clinical Pharmacology, Department of Medicine, University College London, London WC1E 6JF, UK
      72 Department of Cardiovascular Medicine, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
      73 Department of Medicine and Clinical Epidemiology and Biostatistics, Population Genomics Program, McMaster University, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario L8L 2X2, Canada
      74 The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
      75 Department of Pediatrics, University of Pennsylvania, Philadelphia PA 19104, USA
      76 Carolina Center for Genome Sciences, School of Public Health, University of North Carolina, Chapel Hill, NC 27514, USA
      77 Divisions and Endocrinology and Genetics and Program in Genomics, Children's Hospital, Boston, MA 02115, USA
      78 Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
      79 Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
      80 Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD 21201, USA
      81 Pulmonary and Critical Care Unit, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
      82 Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, The Netherlands
      83 Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 55454, USA
      84 Sage Bionetworks, Seattle, WA 98109, USA
      85 Washington University Center for Pharmacogenetics, 660 S. Euclid Ave., Campus Box 8220, St. Louis, MO 63110-1093, USA
      86 Leicester National Institute of Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK
      87 UCL Genetic Institute, University College London, London WC1E 6BT, UK
      88 LURIC Nonprofit LLC, Freiburg, Germany
      89 Synlab Center of Laboratory Diagnostics Heidelberg, Heidelberg D-58509, Germany
      90 Institute of Public Health, Social Medicine and Epidemiology Medical Faculty, University of Heidelberg, D-68167 Mannheim, Germany
      91 Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, A-8036 Graz, Austria
      92 Division of Endocrinology, Diabetes and Metabolism, Centre of Excellence Baden-Wuerttemberg, Metabolic Diseases, Ulm University, D - 89081 Ulm, Germany
      93 Cardiology Group Frankfurt-Sachsenhausen, Frankfurt, Germany
      94 Drug Safety Research Unit, Southampton SO31 1AA, UK
      95 Clinical Pharmacology and the Cambridge Institute of Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0SP, UK
      96 Centre National de Genotypage, CP 5721, 91 057 Evry Cedex, France
      97 JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK
      98 Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, US
      99 Harvard Medical School, Cambridge, MA 02115, USA
      100 Pathology and Laboratory Medicine Institute, Cleveland Clinic Cleveland, OH 44195
      101 International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College London, London W2 1NY, UK
      102 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA
      103 Department of Internal Medicine II – Cardiology, University of Ulm Medical Center, Ulm Konto Nr. 5050, Germany
      104 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
      105 Department of Epidemiology, 1440 Canal Street, Suite 1829, Tulane University, New Orleans, LA 70112-2750, USA
      106 Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet SE-171 77 Stockholm, Sweden
      107 Clinical Trial Service Unit, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX37LF, UK
      108 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TC Utrecht, The Netherlands
      109 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
      110 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, WC1E 7HT, UK
      111 National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive, Suite 1200, Baltimore, MD 21224, USA
      112 Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA
      113 Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
    • Note:
      Published online: December 30, 2010
    • Abstract:
      Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10−6), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10−8). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10−11). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
    • ISSN:
      0002-9297
    • Accession Number:
      10.1016/j.ajhg.2010.11.007
    • Accession Number:
      S000292971000594X
    • Copyright:
      Copyright © 2011 The American Society of Human Genetics Published by Elsevier Inc. All rights reserved.
  • Citations
    • ABNT:
      LANKTREE, M. B. et al. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height. The American Journal of Human Genetics, [s. l.], v. 88, n. 1, p. 6–18, 2011. DOI 10.1016/j.ajhg.2010.11.007. Disponível em: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edselp&AN=S000292971000594X. Acesso em: 26 nov. 2020.
    • AMA:
      Lanktree MB, Guo Y, Murtaza M, et al. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height. The American Journal of Human Genetics. 2011;88(1):6-18. doi:10.1016/j.ajhg.2010.11.007
    • APA:
      Lanktree, M. B., Guo, Y., Murtaza, M., Glessner, J. T., Bailey, S. D., Onland-Moret, N. C., Lettre, G., Ongen, H., Rajagopalan, R., Johnson, T., Shen, H., Nelson, C. P., Klopp, N., Baumert, J., Padmanabhan, S., Pankratz, N., Pankow, J. S., Shah, S., Taylor, K., … Keating, B. J. (2011). Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height. The American Journal of Human Genetics, 88(1), 6–18. https://doi.org/10.1016/j.ajhg.2010.11.007
    • Chicago/Turabian: Author-Date:
      Lanktree, Matthew B., Yiran Guo, Muhammed Murtaza, Joseph T. Glessner, Swneke D. Bailey, N. Charlotte Onland-Moret, Guillaume Lettre, et al. 2011. “Meta-Analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.” The American Journal of Human Genetics 88 (1): 6–18. doi:10.1016/j.ajhg.2010.11.007.
    • Harvard:
      Lanktree, M. B. et al. (2011) ‘Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height’, The American Journal of Human Genetics, 88(1), pp. 6–18. doi: 10.1016/j.ajhg.2010.11.007.
    • Harvard: Australian:
      Lanktree, MB, Guo, Y, Murtaza, M, Glessner, JT, Bailey, SD, Onland-Moret, NC, Lettre, G, Ongen, H, Rajagopalan, R, Johnson, T, Shen, H, Nelson, CP, Klopp, N, Baumert, J, Padmanabhan, S, Pankratz, N, Pankow, JS, Shah, S, Taylor, K, Barnard, J, Peters, BJ, M. Maloney, C, Lobmeyer, MT, Stanton, A, Zafarmand, MH, Romaine, SPR, Mehta, A, van Iperen, EPA, Gong, Y, Price, TS, Smith, EN, Kim, CE, Li, YR, Asselbergs, FW, Atwood, LD, Bailey, KM, Bhatt, D, Bauer, F, Behr, ER, Bhangale, T, Boer, JMA, Boehm, BO, Bradfield, JP, Brown, M, Braund, PS, Burton, PR, Carty, C, Chandrupatla, HR, Chen, W, Connell, J, Dalgeorgou, C, Boer, A de, Drenos, F, Elbers, CC, Fang, JC, Fox, CS, Frackelton, EC, Fuchs, B, Furlong, CE, Gibson, Q, Gieger, C, Goel, A, Grobbee, DE, Hastie, C, Howard, PJ, Huang, G-H, Johnson, WC, Li, Q, Kleber, ME, Klein, BEK, Klein, R, Kooperberg, C, Ky, B, LaCroix, A, Lanken, P, Lathrop, M, Li, M, Marshall, V, Melander, O, Mentch, FD, J. Meyer, N, Monda, KL, Montpetit, A, Murugesan, G, Nakayama, K, Nondahl, D, Onipinla, A, Rafelt, S, Newhouse, SJ, Otieno, FG, Patel, SR, Putt, ME, Rodriguez, S, Safa, RN, Sawyer, DB, Schreiner, PJ, Simpson, C, Sivapalaratnam, S, Srinivasan, SR, et al. 2011, ‘Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height’, The American Journal of Human Genetics, vol. 88, no. 1, pp. 6–18, viewed 26 November 2020, .
    • MLA:
      Lanktree, Matthew B., et al. “Meta-Analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.” The American Journal of Human Genetics, vol. 88, no. 1, Jan. 2011, pp. 6–18. EBSCOhost, doi:10.1016/j.ajhg.2010.11.007.
    • Chicago/Turabian: Humanities:
      Lanktree, Matthew B., Yiran Guo, Muhammed Murtaza, Joseph T. Glessner, Swneke D. Bailey, N. Charlotte Onland-Moret, Guillaume Lettre, et al. “Meta-Analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.” The American Journal of Human Genetics 88, no. 1 (January 7, 2011): 6–18. doi:10.1016/j.ajhg.2010.11.007.
    • Vancouver/ICMJE:
      Lanktree MB, Guo Y, Murtaza M, Glessner JT, Bailey SD, Onland-Moret NC, et al. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height. The American Journal of Human Genetics [Internet]. 2011 Jan 7 [cited 2020 Nov 26];88(1):6–18. Available from: http://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=edselp&AN=S000292971000594X