Research ArticleCardiovascular Genomics

A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease

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Science Translational Medicine  01 Jun 2016:
Vol. 8, Issue 341, pp. 341ra76
DOI: 10.1126/scitranslmed.aad3744

Article Information

vol. 8 no. 341 341ra76

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History: 
  • Received for publication September 9, 2015
  • Accepted for publication May 10, 2016
  • .

Author Information

  1. Robert A. Scott1,*,,
  2. Daniel F. Freitag2,3,*,
  3. Li Li4,*,,
  4. Audrey Y. Chu5,
  5. Praveen Surendran2,
  6. Robin Young2,
  7. Niels Grarup6,
  8. Alena Stancáková7,
  9. Yuning Chen8,
  10. Tibor V. Varga9,
  11. Hanieh Yaghootkar10,
  12. Jian’an Luan1,
  13. Jing Hua Zhao1,
  14. Sara M. Willems1,11,
  15. Jennifer Wessel12,13,
  16. Shuai Wang8,
  17. Nisa Maruthur14,15,16,
  18. Kyriaki Michailidou17,
  19. Ailith Pirie17,
  20. Sven J. van der Lee18,
  21. Christopher Gillson1,
  22. Ali Amin Al Olama17,
  23. Philippe Amouyel19,
  24. Larraitz Arriola20,21,22,
  25. Dominique Arveiler23,
  26. Iciar Aviles-Olmos24,
  27. Beverley Balkau25,26,
  28. Aurelio Barricarte22,27,
  29. Inês Barroso3,28,
  30. Sara Benlloch Garcia17,
  31. Joshua C. Bis29,
  32. Stefan Blankenberg30,
  33. Michael Boehnke31,
  34. Heiner Boeing32,
  35. Eric Boerwinkle33,34,
  36. Ingrid B. Borecki35,
  37. Jette Bork-Jensen6,
  38. Sarah Bowden36,
  39. Carlos Caldas37,
  40. Muriel Caslake38,
  41. The CVD50 consortium,
  42. L. Adrienne Cupples8,39,
  43. Carlos Cruchaga40,
  44. Jacek Czajkowski41,
  45. Marcel den Hoed42,
  46. Janet A. Dunn43,
  47. Helena M. Earl44,
  48. Georg B. Ehret45,
  49. Ele Ferrannini46,
  50. Jean Ferrieres47,
  51. Thomas Foltynie24,
  52. Ian Ford38,
  53. Nita G. Forouhi1,
  54. Francesco Gianfagna48,49,
  55. Carlos Gonzalez50,
  56. Sara Grioni51,
  57. Louise Hiller43,
  58. Jan-Håkan Jansson52,53,
  59. Marit E. Jørgensen54,55,
  60. J. Wouter Jukema56,
  61. Rudolf Kaaks57,
  62. Frank Kee58,
  63. Nicola D. Kerrison1,
  64. Timothy J. Key59,
  65. Jukka Kontto60,
  66. Zsofia Kote-Jarai61,
  67. Aldi T. Kraja41,
  68. Kari Kuulasmaa60,
  69. Johanna Kuusisto62,63,
  70. Allan Linneberg64,65,66,
  71. Chunyu Liu67,
  72. Gaëlle Marenne3,
  73. Karen L. Mohlke68,
  74. Andrew P. Morris69,70,
  75. Kenneth Muir71,72,
  76. Martina Müller-Nurasyid73,74,75,
  77. Patricia B. Munroe76,
  78. Carmen Navarro22,77,
  79. Sune F. Nielsen78,
  80. Peter M. Nilsson79,
  81. Børge G. Nordestgaard78,
  82. Chris J. Packard38,
  83. Domenico Palli80,
  84. Salvatore Panico81,
  85. Gina M. Peloso82,83,84,
  86. Markus Perola60,85,
  87. Annette Peters75,86,
  88. Christopher J. Poole72,87,
  89. J. Ramón Quirós88,
  90. Olov Rolandsson89,
  91. Carlotta Sacerdote90,91,92,
  92. Veikko Salomaa60,
  93. María-José Sánchez22,93,
  94. Naveed Sattar38,
  95. Stephen J. Sharp1,
  96. Rebecca Sims94,
  97. Nadia Slimani95,
  98. Jennifer A. Smith96,
  99. Deborah J. Thompson17,
  100. Stella Trompet56,
  101. Rosario Tumino97,
  102. Daphne L. van der A98,
  103. Yvonne T. van der Schouw99,
  104. Jarmo Virtamo60,
  105. Mark Walker100,
  106. Klaudia Walter3,
  107. GERAD_EC Consortium§,
  108. Neurology Working Group of the Cohorts for Heart,
  109. Aging Research in Genomic Epidemiology (CHARGE),
  110. Alzheimer’s Disease Genetics Consortium§,
  111. Pancreatic Cancer Cohort Consortium,
  112. European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease (EPIC-CVD),
  113. EPIC-InterAct,
  114. Jean E. Abraham101,
  115. Laufey T. Amundadottir102,
  116. Jennifer L. Aponte103,,
  117. Adam S. Butterworth2,
  118. Josée Dupuis8,
  119. Douglas F. Easton17,101,
  120. Rosalind A. Eeles61,104,
  121. Jeanette Erdmann105,
  122. Paul W. Franks9,53,106,
  123. Timothy M. Frayling10,
  124. Torben Hansen6,
  125. Joanna M. M. Howson2,
  126. Torben Jørgensen107,108,109,
  127. Jaspal Kooner110,111,112,
  128. Markku Laakso113,
  129. Claudia Langenberg1,
  130. Mark I. McCarthy70,114,
  131. James S. Pankow115,
  132. Oluf Pedersen6,
  133. Elio Riboli116,
  134. Jerome I. Rotter117,
  135. Danish Saleheen118,
  136. Nilesh J. Samani119,120,
  137. Heribert Schunkert75,121,
  138. Peter Vollenweider122,
  139. Stephen O’Rahilly28,123,124,
  140. CHARGE consortium,
  141. The CHD Exome+ Consortium,
  142. CARDIOGRAM Exome Consortium,
  143. Panos Deloukas125,
  144. John Danesh2,3,
  145. Mark O. Goodarzi126,
  146. Sekar Kathiresan83,127,128,
  147. James B. Meigs129,130,
  148. Margaret G. Ehm103,
  149. Nicholas J. Wareham1, and
  150. Dawn M. Waterworth131,
  1. 1Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
  2. 2Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge CB1 8RN, UK.
  3. 3The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
  4. 4Statistical Genetics, Projects, Clinical Platforms, and Sciences (PCPS), GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
  5. 5Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA.
  6. 6The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  7. 7Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
  8. 8Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA.
  9. 9Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 Malmö, Sweden.
  10. 10Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.
  11. 11Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, 3000 CE Rotterdam, Netherlands.
  12. 12Department of Epidemiology, Fairbanks School of Public Health, Indianapolis, IN 46202, USA.
  13. 13Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
  14. 14Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  15. 15Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD 21205, USA.
  16. 16Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
  17. 17Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
  18. 18Department of Epidemiology, Erasmus University Medical Center, 3000 CA Rotterdam, Netherlands.
  19. 19University of Lille, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, UMR 1167, RID-AGE, F-59000 Lille, France.
  20. 20Public Health Division of Gipuzkoa, San Sebastian 20013, Spain.
  21. 21Instituto BIO-Donostia, Basque Government, San Sebastian 20014, Spain.
  22. 22CIBER Epidemiología y Salud Pública (CIBERESP), Madrid 28029, Spain.
  23. 23Department of Epidemiology and Public Health (EA3430), University of Strasbourg, 67085 Strasbourg, France.
  24. 24Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.
  25. 25INSERM, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), 94807 Villejuif, France.
  26. 26Univeristy of Paris-Sud, F-94805 Villejuif, France.
  27. 27Navarre Public Health Institute (ISPN), Pamplona 31003, Spain.
  28. 28University of Cambridge Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, Cambridge CB2 0QQ, UK.
  29. 29Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
  30. 30Department of General and Interventional Cardiology, University Heart Center Hamburg, 20246 Hamburg, Germany.
  31. 31Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109–2029, USA.
  32. 32German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
  33. 33Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77025, USA.
  34. 34Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
  35. 35Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63108, USA.
  36. 36Cancer Research UK Clinical Trials Unit, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
  37. 37Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK.
  38. 38University of Glasgow, Glasgow G12 8QQ, UK.
  39. 39Framingham Heart Study, National Heart, Lung, and Blood Institute (NHLBI), Framingham, MA 01702–5827, USA.
  40. 40Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
  41. 41Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
  42. 42Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, SE-752 37 Uppsala, Sweden.
  43. 43Warwick Clinical Trials Unit, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.
  44. 44University of Cambridge and National Institute of Health Research Cambridge Biomedical Research Centre, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge CB2 0QQ, UK.
  45. 45McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
  46. 46Consiglio Nazionale delle Ricerche (CNR), Institute of Clinical Physiology, 56124 Pisa, Italy.
  47. 47Department of Epidemiology, UMR 1027, INSERM, Centre Hospitalier Universitaire (CHU) de Toulouse, 31000 Toulouse, France.
  48. 48Department of Clinical and Experimental Medicine, Research Centre in Epidemiology and Preventive Medicine, University of Insubria, 21100 Varese, Italy.
  49. 49Department of Epidemiology and Prevention, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Neurologico Mediterraneo Neuromed, 86077 Pozzilli, Italy.
  50. 50Catalan Institute of Oncology (ICO), Barcelona 08908, Spain.
  51. 51Epidemiology and Prevention Unit, 20133 Milan, Italy.
  52. 52Research Unit, 931 41 Skellefteå, Sweden.
  53. 53Department of Public Health & Clinical Medicine, Umeå University, 901 85 Umeå, Sweden.
  54. 54Steno Diabetes Center, 2820 Gentofte, Denmark.
  55. 55National Institute of Public Health, Southern Denmark University, DK-1353 Odense, Denmark.
  56. 56Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
  57. 57German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.
  58. 58UK Clinical Research Collaboration (UKCRC) Centre of Excellence for Public Health, Queen’s University Belfast, Northern Ireland, Belfast BT12 6BJ, UK.
  59. 59University of Oxford, Oxford OX1 2JD, UK.
  60. 60National Institute for Health and Welfare, FI-00271 Helsinki, Finland.
  61. 61The Institute of Cancer Research, London SM2 5NG, UK.
  62. 62Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, FI-70211 Kuopio, Finland.
  63. 63Kuopio University Hospital, FL 70029 Kuopio, Finland.
  64. 64Research Centre for Prevention and Health, Capital Region, DK-2600 Copenhagen, Denmark.
  65. 65Department of Clinical Experimental Research, Rigshospitalet, 2100 Glostrup, Denmark.
  66. 66Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
  67. 67Framingham Heart Study, Population Sciences Branch, NHLBI/National Institutes of Health (NIH), Bethesda, MD 20892, USA.
  68. 68Department of Genetics, University of North Carolina, Chapel Hill, NC 27599–7264, USA.
  69. 69Department of Biostatistics, University of Liverpool, Liverpool L69 3GL, UK.
  70. 70Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  71. 71Centre for Epidemiology, Institute of Population Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
  72. 72University of Warwick, Coventry CV4 7AL, UK.
  73. 73Institute of Genetic Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
  74. 74Department of Medicine I, Ludwig Maximilians University Munich, 80336 Munich, Germany.
  75. 75DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, 80802 Munich, Germany.
  76. 76Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
  77. 77Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia 30008, Spain.
  78. 78Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, 2730 Copenhagen, Denmark.
  79. 79Lund University, 20502 Malmö, Sweden.
  80. 80Cancer Research and Prevention Institute (ISPO), 50141 Florence, Italy.
  81. 81Dipartimento di Medicina Clinica e Chirurgia, Federico II University, 80131 Naples, Italy.
  82. 82Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
  83. 83Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
  84. 84Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
  85. 85Institute of Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014 Helsinki, Finland.
  86. 86Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
  87. 87Department of Medical Oncology, Arden Cancer Centre, University Hospital Coventry and Warwickshire, West Midlands CV2 2DX, UK.
  88. 88Public Health Directorate, 33006 Oviedo, Asturias, Spain.
  89. 89Umeå University, 90187 Umeå, Sweden.
  90. 90Unit of Cancer Epidemiology, Citta’ della Salute e della Scienza Hospital, University of Turin, 10126 Torino, Italy.
  91. 91Center for Cancer Prevention (CPO), 10126 Torino, Italy.
  92. 92Human Genetics Foundation, 10126 Torino, Italy.
  93. 93Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada/Universidad de Granada, Granada 18012, Spain.
  94. 94Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre, Cardiff University, Cardiff CF24 4HQ, UK.
  95. 95International Agency for Research on Cancer, 69372 Lyon, France.
  96. 96Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109–2029, USA.
  97. 97Cancer Registry and Histopathology Unit, “Civic–M.P. Arezzo” Hospital, ASP Ragusa, 97100 Ragusa, Italy.
  98. 98National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, Netherlands.
  99. 99University Medical Center Utrecht, 3508 GA Utrecht, Netherlands.
  100. 100Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
  101. 101Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.
  102. 102Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  103. 103Genetics, PCPS, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
  104. 104Royal Marsden NHS Foundation Trust, Fulham and Sutton, London and Surrey SW3 6JJ, UK.
  105. 105Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, 23562 Lübeck, Germany.
  106. 106Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
  107. 107Research Centre for Prevention and Health, DK-2600 Capital Region, Denmark.
  108. 108Department of Public Health, Institute of Health Science, University of Copenhagen, 1014 Copenhagen, Denmark.
  109. 109Faculty of Medicine, Aalborg University, 9220 Aalborg, Denmark.
  110. 110National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
  111. 111Imperial College Healthcare NHS Trust, London W2 1NY, UK.
  112. 112Ealing Hospital NHS Trust, Middlesex UB1 3HW, UK.
  113. 113Department of Medicine, University of Kuopio, FI-70211 Kuopio, Finland.
  114. 114Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, UK.
  115. 115Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455–0381, USA.
  116. 116School of Public Health, Imperial College London, London W2 1PG, UK.
  117. 117Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor–University of California, Los Angeles Medical Center, Torrance, CA 90502, USA.
  118. 118Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
  119. 119Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.
  120. 120National Institute for Health Research, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK.
  121. 121Deutsches Herzzentrum München, Technische Universität München, 80636 Munich, Germany.
  122. 122Department of Internal Medicine, BH10-462, Internal Medicine, Lausanne University Hospital (CHUV), CH-1011 Lausanne, Switzerland.
  123. 123MRC Metabolic Diseases Unit, Cambridge CB2 0QQ, UK.
  124. 124National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK.
  125. 125William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
  126. 126Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  127. 127Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  128. 128Cardiology Division, Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  129. 129Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  130. 130Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  131. 131Genetics, PCPS, GlaxoSmithKline, Philadelphia, PA 19104, USA.
  1. Corresponding author. Email: dawn.m.waterworth{at}gsk.com (D.M.W.); robert.scott{at}mrc-epid.cam.ac.uk (R.A.S.); nick.wareham{at}mrc-epid.cam.ac.uk (N.J.W.)
  • * These authors contributed equally to this work.

  • Present address: PAREXEL, Durham, NC 27713, USA.

  • § Data used in the preparation of this article were obtained from the Genetic and Environmental Risk for Alzheimer’s Disease_Exome Chip (GERAD_EC) Consortium and Alzheimer’s Disease Genetics Consortium (ADGC). As such, the investigators within the GERAD_EC Consortium and ADGC contributed to the design and implementation of GERAD_EC and ADGC and/or provided data but did not participate in the analysis or writing of this report.

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