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Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height
Authors:Lanktree Matthew B  Guo Yiran  Murtaza Muhammed  Glessner Joseph T  Bailey Swneke D  Onland-Moret N Charlotte  Lettre Guillaume  Ongen Halit  Rajagopalan Ramakrishnan  Johnson Toby  Shen Haiqing  Nelson Christopher P  Klopp Norman  Baumert Jens  Padmanabhan Sandosh  Pankratz Nathan  Pankow James S  Shah Sonia  Taylor Kira  Barnard John  Peters Bas J  Maloney Cliona M  Lobmeyer Maximilian T  Stanton Alice  Zafarmand M Hadi  Romaine Simon P R  Mehta Amar  van Iperen Erik P A  Gong Yan  Price Tom S  Smith Erin N  Kim Cecilia E  Li Yun R  Asselbergs Folkert W  Atwood Larry D  Bailey Kristian M  Bhatt Deepak  Bauer Florianne
Institution:1Department of Medicine and Biochemistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada;2Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA;3Beijing Genomics Institute at Shenzhen, Shenzhen, China;4Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK;5Montréal Heart Institute, Université de Montréal, Montréal, Québec, H1T 1C8, Canada;6Department of Human Genetics, McGill University, Montréal, Québec, H3A 1B1, Canada;7Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London WC1E 6BT, UK;8The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK;9Clinical 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;10Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, 98195, USA;11Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, 21201, USA;12Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany;13Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA;14Department of Quantitative Health Sciences, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA;15Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK;16Center for Pharmacogenomics, College of Pharmacy, University of Florida, FL 32610 USA;17Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705 USA;18Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands;19Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA;20MRC SGDP Centre, Institute of Psychiatry, London SE5 8AF, UK;21Complex Genetics Section, Department of Medical Genetics (DBG) University Medical Center Utrecht, Utrecht STR 6, The Netherlands;22Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands;23Leeds Institute of Genetics Health & Therapeutics, University of Leeds, Leeds LS2 9JT, UK;24Department of Medical and Molecular Genetics, Indiana University, School of Medicine, 410 West 10th Street, HS4000, Indianapolis, IN 46202, USA;25Department of Environmental Health, Environmental and Occupational Medicine and Epidemiology Program, Harvard School of Public Health, Boston, MA 02115 USA;26Department of Cardiology and Vascular Medicine, Academic Medical Center, 1105 AZ Amsterdam;27Centre for Cardiovascular Genetics, Department of Medicine, University College London, 5 University Street, London WC1E 6JF, UK;28National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands;29Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA;30Department of Genetics, Rosetta Inpharmatics, Seattle, WA 98109-5234, USA;31Scripps Genomic Medicine and Scripps Translational Science Institute, 3344 N. Torrey Pines Ct. Ste 300, La Jolla, CA 92037, USA;32Department of Health Sciences, University of Leicester, Adrian Building, University Rd., Leicester LE1 7RH, UK;33Department of Clinical Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH 44106, USA;34Department of Biostatistics, University of Washington, Seattle, WA 98195 USA;35Framingham Heart Study, Boston University School of Medicine, Boston, MA 02118-2526, USA;36University of Pennsylvania Medical Center, Pulmonary, Allergy & Critical Care Division, Philadelphia, PA 19104-6160, USA;37Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto St., Pittsburgh, PA 15261, USA;38University of Dundee, Medical School, Ninewells Hospital and Medical School, DD1 9SY Dundee, UK;39Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 55454, USA;40Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC 27514, USA;41Harvard Medical School, Brigham and Women's Hospital and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA;42McGill University and Genome Québec Innovation Centre, Montréal, Québec H3A 1A4 Canada;43Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco;44Broad Institute of MIT and Harvard, Cambridge, MA 02115, USA;45Division of Cardiovascular Sciences, St George's University of London, London SW17 0RE, UK;46Division of Clinical Developmental Sciences, St George's University of London SW17 0RE, London, UK;47Cardiovascular Medicine, University of Wisconsin, Madison, WI 53792, USA;48Cardiovascular Division, Vanderbilt University Medical Center, Nashville, TN 37232, USA;49Department of Molecular Medicine, Boston University, Boston, MA 02118, USA;50Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA;51Cardiovascular Medicine, Case Western Reserve University, Cleveland, OH 44106,USA;52Institute of Statistics, National Chiao Tung University, Hsinchu 30010, Taiwan;53MRC Centre for Causal Analyses in Translational Epidemiology, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK;54BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow G12 8TA, UK;55Clinical Research Center (CRC), Malmö University Hospital, SE-205 02 Malmö, Sweden;56Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Place, Glasgow G12 8QQ, UK;57Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland;58Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland;59Translational Genomics Research Institute, Phoenix, AZ 85004, USA;60TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA;61Department 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;62Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA;63Molecular Genetics, University Medical Center Groningen, Groningen University, Groningen 9700 RB, the Netherlands;64Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida College of Pharmacy, Gainesville, FL 32610, USA;65Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK;66Center for Non-Communicable Diseases, Karachi, Pakistan;67Departments of Medicine and Human Genetics, McGill University, Montréal, Québec H3A 1B1, Canada;68Human Genetics Center and Div. of Epidemiology, 1200 Herman Pressler, Suite E-447, Houston, TX 77030, USA;69Department of Genetics, University Medical Center Groningen and Groningen University, 9700 RB Groningen, The Netherlands;70National Heart, Lung, and Blood Institute (NHLBI), Division of Cardiovascular Sciences, Bethesda, MD 20892, USA;71Centre for Clinical Pharmacology, Department of Medicine, University College London, London WC1E 6JF, UK;72Department of Cardiovascular Medicine, University of Oxford, Level 6 West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK;73Department of Medicine and Clinical Epidemiology and Biostatistics, Population Genomics Program, McMaster University, Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario L8L 2X2, Canada;74The Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;75Department of Pediatrics, University of Pennsylvania, Philadelphia PA 19104, USA;76Carolina Center for Genome Sciences, School of Public Health, University of North Carolina, Chapel Hill, NC 27514, USA;77Divisions and Endocrinology and Genetics and Program in Genomics, Children's Hospital, Boston, MA 02115, USA;78Department of Genetics, Harvard Medical School, Boston, MA 02115, USA;79Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA;80Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, MD 21201, USA;81Pulmonary and Critical Care Unit, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA;82Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, 1007 MB Amsterdam, The Netherlands;83Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, MN 55454, USA;84Sage Bionetworks, Seattle, WA 98109, USA;85Washington University Center for Pharmacogenetics, 660 S. Euclid Ave., Campus Box 8220, St. Louis, MO 63110-1093, USA;86Leicester National Institute of Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK;87UCL Genetic Institute, University College London, London WC1E 6BT, UK;88LURIC Nonprofit LLC, Freiburg, Germany;89Synlab Center of Laboratory Diagnostics Heidelberg, Heidelberg D-58509, Germany;90Institute of Public Health, Social Medicine and Epidemiology Medical Faculty, University of Heidelberg, D-68167 Mannheim, Germany;91Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, A-8036 Graz, Austria;92Division of Endocrinology, Diabetes and Metabolism, Centre of Excellence Baden-Wuerttemberg, Metabolic Diseases, Ulm University, D - 89081 Ulm, Germany;93Cardiology Group Frankfurt-Sachsenhausen, Frankfurt, Germany;94Drug Safety Research Unit, Southampton SO31 1AA, UK;95Clinical Pharmacology and the Cambridge Institute of Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0SP, UK;96Centre National de Genotypage, CP 5721, 91 057 Evry Cedex, France;97JDRF/WT Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK;98Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037, US;99Harvard Medical School, Cambridge, MA 02115, USA;100Pathology and Laboratory Medicine Institute, Cleveland Clinic Cleveland, OH 44195;101International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College London, London W2 1NY, UK;102Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA;103Department of Internal Medicine II – Cardiology, University of Ulm Medical Center, Ulm Konto Nr. 5050, Germany;104Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands;105Department of Epidemiology, 1440 Canal Street, Suite 1829, Tulane University, New Orleans, LA 70112-2750, USA;106Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet SE-171 77 Stockholm, Sweden;107Clinical Trial Service Unit, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX37LF, UK;108Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3508 TC Utrecht, The Netherlands;109Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands;110Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, WC1E 7HT, UK;111National Human Genome Research Institute, National Institutes of Health, 333 Cassell Drive, Suite 1200, Baltimore, MD 21224, USA;112Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA;113Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
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.
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